Substituted 4-(1.2,3,4-tetrahydroisoquinolin-2-yl)-4-oxobutyric acid amide as KCNQ2/3 modulators

ABSTRACT

The invention relates to substituted tetrahydroisoquinolinyl-4-oxobutyric acid amides, methods for the preparation thereof, medicinal products containing these compounds and the use of these compounds for the preparation of medicinal products.

This application claims priority under 35 U.S.C. §119 of EP ApplicationNo. 08021880.3, filed Dec. 17, 2008, and under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/138,269, filed Dec. 17, 2008.

The invention relates to substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amides, methods for thepreparation thereof, medicinal products containing these compounds andthe use of these compounds for the preparation of medicinal products.

The treatment of pain, in particular neuropathic pain, is of greatimportance in medicine. There is a worldwide need for effective paintherapies. The urgent need for action to find targeted,patient-appropriate treatment for chronic and non-chronic painconditions, this being understood as the successful and satisfactorytreatment of pain for the patient, is also documented in the largenumber of scientific works that have been published in recent times inthe field of applied analgesics and basic research into nociception.

A pathophysiological feature of chronic pain is the overexcitability ofneurons. Neuronal excitability is decisively influenced by the activityof K⁺ channels, since these significantly determine the restingpotential of the cell and hence the excitability threshold. HeteromericK⁺ channels of the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressedin neurons of various regions of the central (hippocampus, amygdala) andperipheral (dorsal root ganglia) nervous system and regulate theexcitability thereof. Activation of KCNQ2/3 K⁺ channels leads to ahyperpolarisation of the cell membrane and, accompanying this, to adecrease in the electrical excitability of these neurons.KCNQ2/3-expressing neurons of the dorsal root ganglia are involved inthe transmission of nociceptive stimuli from the periphery into thespinal cord (Passmore et al., J Neurosci. 2003; 23(18):7227-36).

It has accordingly been possible to detect an analgesic activity inpreclinical neuropathic and inflammatory pain models for the KCNQ2/3agonist retigabine (Blackburn-Munro and Jensen, Eur J Pharmacol. 2003;460(2-3):109-16; post et al., Naunyn Schmiedeberg's Arch Pharmacol 2004;369(4): 382-390).

The KCNQ2/3 K⁺ channel thus represents a suitable starting point for thetreatment of pain; in particular pain chosen from the group consistingof chronic pain, neuropathic pain, inflammatory pain and muscular pain(Nielsen et al., Eur J Pharmacol. 2004; 487(1-3): 93-103), in particularneuropathic and inflammatory pain.

Moreover, the KCNQ2/3 K⁺ channel is a suitable target for therapy of alarge number of further diseases, such as, for example, migraine(US2002/0128277), cognitive diseases (Gribkoff, Expert Opin Ther Targets2003; 7(6): 737-748), anxiety states (Korsgaard et al., J Pharmacol ExpTher. 2005, 14(1): 282-92), epilepsy (Wickenden et al., Expert Opin TherPat 2004; 14(4): 457-469; Gribkoff, Expert Opin Ther Targets 2008,12(5): 565-81; Miceli et al., Curr Opin Pharmacol 2008, 8(1): 65-74),urinary incontinence (Streng et al., J Urol 2004; 172: 2054-2058),dependency (Hansen et al., Eur J Pharmacol 2007, 570(1-3): 77-88),mania/bipolar disorders (Dencker et al., Epilepsy Behav 2008, 12(1):49-53), dystonia-associated dyskinesias (Richter et al., Br J Pharmacol2006, 149(6): 747-53).

Substituted tetrahydropyrrolopyrazines having an affinity for theKCNQ2/3 K⁺ channel are known from the prior art (WO 2008/046582).

There is a need for further compounds having comparable or betterproperties, not only in regard to affinity for KCNQ2/3 as such (potency,efficacy).

For instance, it can be advantageous to improve the metabolic stability,the solubility in aqueous media or the permeability of the compounds.These factors can have a beneficial effect on oral bioavailability orcan alter the PK/PD (pharmacokinetic/pharmacodynamic) profile, which canlead to a more favourable period of action, for example.

A weak or non-existent interaction with transporter molecules, which areinvolved in the uptake and excretion of medicinal products, can also betaken as an indication of improved bioavailability and at most lowmedicinal product interaction. Furthermore, interactions with theenzymes involved in the breakdown and excretion of medicinal productsshould also be as low as possible, since such test results likewiseindicate that at most low or even no medicinal product interactionswhatsoever are to be anticipated.

It can further be advantageous if the compounds exhibit a highselectivity towards other receptors of the KCNQ family (specificity),for example towards KCNQ1, KCNQ3/5 or KCNQ4. A high selectivity can havea favourable effect on the side-effects profile. It is known, forexample, that compounds which (also) bind to KCNQ1 are associated with ahigh risk of cardiac side effects, for which reason a high selectivitytowards KCNQ1 can be desirable. A high selectivity towards otherreceptors can also be advantageous, however. A low affinity to the hERGion channel or to the L-type calcium ion channel (phenyl alkylamine,benzothiazepine, dihydropyridine binding sites) can be advantageous, asthese receptors are associated with the occurrence of cardiac sideeffects. Overall an improved selectivity with regard to binding to otherendogenous proteins (i.e. receptors or enzymes for example) can lead toan improvement in the side-effects profile and hence to an improvedcompatibility.

An object of the invention was therefore to provide novel compoundshaving advantages over the prior art compounds. The compounds should inparticular be suitable as pharmacological active ingredients inmedicinal products, preferably in medicinal products for the treatmentof disorders or diseases which are at least partly mediated by KCNQ2/3K⁺ channels.

This object is achieved by the subject matter of the claims.

Surprisingly it has been found that substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amides having the generalformula (1) given below are suitable for the treatment of pain. It hasfurther surprisingly been found that substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amides having the generalformula (1) given below also have an excellent affinity for the KCNQ2/3K⁺ channel and are therefore suitable for the treatment of disorders ordiseases which are at least partly mediated by KCNQ2/3 K⁺ channels. Thesubstituted tetrahydroisoquinolinyl-4-oxobutyric acid amides act here asmodulators, i.e. agonists or antagonists, of the KCNQ2/3 K⁺ channel.

The invention provides substituted tetrahydroisoquinolinyl-4-oxobutyricacid amides having the general formula (1)

whereinR⁰ stands for C₁₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; aryl orheteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₁₋₈alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;R¹ stands for F; Cl; Br; CN; C₁₋₁₀ alkyl, preferably C₁₋₆ alkyl, orC₂₋₁₀ heteroalkyl, each saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; C₃₋₇ cycloalkyl,preferably C₃₋₆ cycloalkyl, or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; aryl orheteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl, preferably C₃₋₆ cycloalkyl, orheterocyclyl, each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; C₁₋₈ alkyl-bridged heteroaryl, unsubstituted or mono-or polysubstituted, wherein the alkyl chain can be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or C₁₋₈ alkyl-bridged aryl, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be unbranched, saturated orunsaturated, unsubstituted;R² stands for H; F; Cl; Br; or C₁₋₁₀ alkyl, saturated or unsaturated,branched or unbranched, unsubstituted or mono- or polysubstituted;or R¹ and R² together with the carbon atom binding them as ring memberform a C₃₋₇ cycloalkyl, preferably C₃₋₆ cycloalkyl, or heterocyclyl,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, each optionally fused to (hetero)aryl, unsubstituted ormono- or polysubstituted;R³, R⁴, R⁵ and R⁶ each mutually independently denote H; F; Cl; Br; I;NO₂; CF₃; CN; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)R⁰; CONH₂; C(═O)NHR⁰;C(═O)N(R⁰)₂; OH; OR⁰; —O—(C₁₋₈ alkyl)-O—; O—C(═O)—R⁰; O—C(═O)—O—R⁰;O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰;O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂;NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R)₂; NR⁰—S(═O)₂OH;NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰;NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰;S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R)₂;R⁷, R⁸, R⁹, R¹⁹ mutually independently stand for H; F; Cl; Br; C₁₋₁₀alkyl, saturated or unsaturated, branched or unbranched, unsubstitutedor mono- or polysubstituted;R¹¹ stands for H; F; Cl; Br; CN; R⁰;R¹² stands for H; F; Cl; Br; CN; or C₁₋₁₀ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted;R¹³ stands for H; F; Cl; Br; CN; C₁₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, eachsaturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; aryl orheteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₂₋₈alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;R¹⁴ stands for H; F; Cl; Br; CN; or C₁₋₁₀ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted;or R¹¹ and R¹³ together with the carbon atoms binding them as ringmembers form a C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, optionally fusedto (hetero)aryl, unsubstituted or mono- or polysubstituted;or R¹¹ and R¹²; or R¹³ and R¹⁴, together with the carbon atoms bindingthem as ring members form a C₃₋₇ cycloalkyl or heterocyclyl, eachsaturated or unsaturated, unsubstituted or mono- or polysubstituted,each optionally fused to (hetero)aryl, unsubstituted or mono- orpolysubstituted;R¹⁵ stands for R⁰;wherein “alkyl-substituted”, “heteroalkyl-substituted”,“heterocyclyl-substituted” and “cycloalkyl-substituted” stand for thesubstitution of one or more hydrogen atoms, each mutually independently,with F; Cl; Br; I; CN; CF₃; ═O; ═NH; ═C(NH₂)₂; NO₂; R⁰; C(═O)H; C(═O)R⁰;CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; O—(C₁₋₈alkyl)-O; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰;S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; S(═O)₂N(R⁰)₂;wherein “aryl-substituted” and “heteroaryl-substituted” stand for thesubstitution of one or more hydrogen atoms, each mutually independently,with F; Cl; Br; I; NO₂; CF₃; CN; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; S(═O)₂N(R⁰)₂;in the form of the free compounds or salts of physiologically compatibleacids or bases.

Within the meaning of this invention the expressions “C₁₋₂ alkyl”, “C₁₋₄alkyl”, “C₁₋₆ alkyl”, “C₁₋₈ alkyl”, “C₁₋₁₀ alkyl”, “C₂₋₄ alkyl” and“C₂₋₈ alkyl” include acyclic saturated or unsaturated hydrocarbonradicals, which can be branched or unbranched and unsubstituted or mono-or polysubstituted, having 1 to 2 or 1 to 4 or 1 to 8 or 1 to 10 or 2 to4 or 2 to 8 C atoms respectively, i.e. C₁₋₂ alkanyls and C₁₋₂ alkenylsor C₁₋₄ alkanyls, C₁₋₄ alkenyls and C₂₋₄ alkynyls or C₁₋₈ alkanyls, C₁₋₈alkenyls and C₂₋₈ alkynyls or C₁₋₁₀ alkanyls, C₁₋₁₀ alkenyls and C₂₋₁₀alkynyls or C₂₋₄ alkanyls, C₂₋₄-alkenyls and C₂₋₄ alkynyls or C₂₋₈alkanyls, C₂₋₈ alkenyls and C₂₋₈ alkynyls. Alkenyls have at least oneC—C double bond and alkynyls have at least one C—C triple bond. Alkyl ispreferably selected from the group comprising methyl, ethyl, n-propyl,2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, ethylenyl(vinyl), ethynyl, propenyl (—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃),propynyl (—CH—C≡CH, —C≡C—CH₃), butenyl, butynyl, pentenyl, pentynyl,hexenyl and hexynyl, heptenyl, heptynyl, octenyl, octynyl, nonenyl,nonynyl, decenyl and decynyl.

Within the meaning of this invention the expression “C₂₋₁₀ heteroalkyl”includes acyclic saturated or unsaturated hydrocarbon radicals having 2to 10 C atoms, i.e. C₂₋₁₀ heteroalkanyls, C₂₋₁₀ heteroalkenyls and C₂₋₁₀heteroalkynyls, each of which can be branched or unbranched andunsubstituted or mono- or polysubstituted and in which one, two or threecarbon atoms are replaced by a heteroatom or a heteroatom group, eachmutually independently selected from the group consisting of O, N, NH,N(C₁₋₄ alkyl), preferably N(CH₃), S, S(═O) and S(═O)₂, wherein both theinitial and also the terminal carbon atom of a C₂₋₁₀ heteroalkyls cannotbe replaced by a heteroatom or a heteroatom group and adjacent carbonatoms cannot simultaneously be replaced by a heteroatom or a heteroatomgroup. One, two or three carbon atoms of a C₂₋₁₀ heteroalkyl arepreferably replaced by a heteroatom or a heteroatom group, each mutuallyindependently selected from the group consisting of O, N and S.Furthermore each heteroatom or each heteroatom group must have at leasttwo carbon atoms as binding partners. C₂₋₁₀ heteroalkenyls have at leastone C—C or one C—N double bond and C₂₋₁₀ heteroalkynyls have at leastone C—C triple bond. C₂₋₁₀ heteroalkyl is preferably selected from thegroup consisting of —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CH₂—CH₃,—CH₂—CH₂—O—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₂—CH₃,—CH₂—CH₂—NH—CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—N(CH₃)—CH₂—CH₃,—CH₂—CH₂—N(CH₃)—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₃, —CH₂—CH₂—S—CH₂—CH₃,—CH₂—CH₂—S—CH₂—CH₂—S—CH₃, —CH₂—CH₂—NH—CH₂—CH₂—O—CH₃ and —CH₂═N(CH₃).

For the purposes of this invention the expression “cycloalkyl”, “C₃₋₇cycloalkyl” or “C₃₋₆ cycloalkyl” denotes cyclic hydrocarbons having 3,4, 5, 6 or optionally 7 carbon atoms, wherein the hydrocarbons can besaturated or unsaturated (but not aromatic), unsubstituted or mono- orpolysubstituted. The binding of the cycloalkyl to the higher-ordergeneral structure can be made via any desired and possible ring memberof the cycloalkyl radical. The cycloalkyl radicals can also be fused tofurther saturated, (partially) unsaturated, heterocyclic, aromatic orheteroaromatic ring systems, which can in turn be unsubstituted or mono-or polysubstituted. The cycloalkyl radicals can further be singly ormultiply bridged, as for example in the case of adamantyl ordicyclopentadienyl. C₃₋₇ cycloalkyl is preferably selected from thegroup including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “heterocyclyl” includes saturated or unsaturated (but notaromatic) cycloalkyls having three to seven ring members, in which one,two or three carbon atoms can be replaced by a heteroatom, each mutuallyindependently selected from the group S, N or O, wherein the ringmembers can be unsubstituted or mono- or polysubstituted. The binding ofthe heterocyclyl to the higher-order general structure can be made viaany desired and possible ring member of the heterocyclyl radical. Theheterocyclyl radicals can also be fused to further saturated,(partially) unsaturated or aromatic or heteroaromatic ring systems,which can in turn be unsubstituted or mono- or polysubstituted.Heterocyclyl radicals from the group comprising azetidinyl, aziridinyl,azepanyl, quinolinyl, dioxanyl, dioxolanyl, furanyl, imidazolidinyl,isoxazolidinyl, isoquinolinyl, indolinyl, morpholinyl, pyranyl,pyrrolyl, pyridinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl,pyrazolidinyl, pyrazolinonyl or thiomorpholinyl are preferred.

Within the meaning of this invention, the term “aryl” denotes aromatichydrocarbons having up to 14 ring members, inter alia phenyls andnaphthyls. Each aryl radical can be present in unsubstituted or mono- orpolysubstituted form, wherein the aryl substituents can be identical ordifferent and can be at any desired and possible position of the aryl.The binding of the aryl to the higher-order general structure can bemade via any desired and possible ring member of the aryl radical. Thearyl radicals can also be fused to further saturated, (partially)unsaturated, heterocyclic, aromatic or heteroaromatic ring systems,which can in turn be unsubstituted or mono- or polysubstituted. Aryl ispreferably selected from the group including phenyl, 1-naphthyl and2-naphthyl, each of which can be unsubstituted or mono- orpolysubstituted. A particularly preferred aryl is phenyl, unsubstitutedor mono- or polysubstituted.

The term “heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromaticradical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms,wherein the heteroatoms can each be mutually independently selected fromthe group S, N or O and the heteroaryl radical can be unsubstituted ormono- or polysubstituted; if the heteroaryl is substituted, thesubstituents can be identical or different and can be at any desired andpossible position of the heteroaryl. Preferred heteroatoms are S, N andO, S and N are particularly preferred. The binding to the higher-ordergeneral structure can be made via any desired and possible ring memberof the heteroaryl radical. The heteroaryl can also be part of a bicyclicor polycyclic system having up to 14 ring members, wherein the ringsystem can be formed with further saturated, (partially) unsaturated,heterocyclic or aromatic or heteroaromatic rings, which can in turn beunsubstituted or mono- or polysubstituted. The heteroaryl radical ispreferably selected from the group comprising benzofuranyl,benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzotriazolyl, benzodioxolanyl, benzodioxanyl, quinazolinyl,carbazolyl, quinolinyl, furyl (furanyl), imidazolyl, indazolyl,indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl,oxadiazolyl, phthalazinyl, pyrazolyl, pyridyl, pyrrolyl, pyridazinyl,pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl, triazolyl,thiazolyl, thiadiazolyl or triazinyl. Pyridyl, thienyl, indolyl andindazolyl are particularly preferred.

Within the meaning of the invention the expressions “C₁₋₂ alkyl- or C₁₋₄alkyl- or C₁₋₈ alkyl- or C₂₋₈ alkyl-bridged aryl, heteroaryl,heterocyclyl or cycloalkyl” mean that C₁₋₂ alkyl or C₁₋₄ alkyl or C₁₋₈alkyl or C₂₋₈ alkyl and aryl or heteroaryl or heterocyclyl or cycloalkylhave the meanings defined above and the aryl or heteroaryl orheterocyclyl or cycloalkyl radical is bound by a C₁₋₂ alkyl or a C₁₋₄alkyl or a C₁₋₈ alkyl or a C₂₋₈ alkyl group to the higher-order generalstructure. The alkyl chain can in all cases be saturated or unsaturated,branched or unbranched, unsubstituted or mono- or polysubstituted.

In connection with “alkyl”, “heteroalkyl”, “heterocyclyl” and“cycloalkyl” the term “mono- or polysubstituted” within the meaning ofthis invention is understood to mean the single or multiple, e.g. two,three or four times, substitution of one or more hydrogen atoms eachmutually independently with substituents selected from the groupcomprising F; Cl; Br; I; CN; CF₃; ═O; ═NH; ═C(NH₂)₂; NO₂; R⁰; C(═O)H;C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰;—O—(C₁₋₈ alkyl)-O—; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰;O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂;O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰;NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂;NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰;NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂;NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰;NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰;S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰;S(═O)₂N(R⁰)₂, wherein polysubstituted radicals are understood to beradicals which are substituted multiple times, for example twice, threeor four times, at different or the same atoms, for example substitutedthree times at the same C atom, as in the case of CF₃ or CH₂CF₃, or atdifferent points, as in the case of CH(OH)—CH═CH—CHCl₂. A substituentcan in turn itself optionally be mono- or polysubstituted. Thepolysubstitution can be performed with identical or differentsubstituents.

Preferred “alkyl”, “heteroalkyl”, “heterocyclyl” and “cycloalkyl”substituents are F; Cl; Br; I; NO₂; CF₃; CN; ═O; ═NH; R⁰; C(═O)(R⁰ orH); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O;O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰ or H)₂; N(R⁰ or H)—C(═O)—R⁰;N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃; SR⁰; S(═O)₂R⁰; S(═O)₂O(R⁰ or H);S(═O)₂—N(R⁰ or H)₂.

The expression “(R⁰ or H)” within a radical means that R⁰ and H canoccur within this radical in any possible combination. Thus the radical“N(R⁰ or H)₂” can stand for “NH₂”, “NHR⁰” and “N(R⁰)₂”, for example. IfR⁰ occurs more than once within a radical, as in the case of “N(R⁰)₂”,then R⁰ can have the same or different meanings in each case: in thepresent example of “N(R⁰)₂”, for example, R⁰ can stand twice for aryl,giving the functional group “N(aryl)₂”, or R⁰ can stand once for aryland once for C₁₋₁₀ alkyl, giving the functional group “N(aryl)(C₁₋₁₀alkyl)”.

In connection with “aryl” and “heteroaryl” the expression “mono- orpolysubstituted” within the meaning of this invention is understood tomean the single or multiple, e.g. two, three or four times, substitutionof one or more hydrogen atoms in the ring system, each mutuallyindependently with substituents selected from the group comprising F;Cl; Br; I; NO₂; CF₃; CN; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; S(═O)₂N(R⁰)₂, at one or optionallydifferent atoms, wherein a substituent can in turn itself optionally bemono- or polysubstituted. The polysubstitution is performed withidentical or with different substituents.

Preferred “aryl” and “heteroaryl” substituents are F; Cl; Br; I; NO₂;CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰;—O—(C₁₋₈ alkyl)-O—; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰ or H)₂; N(R⁰or H)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃; SR⁰; S(═O)₂R⁰;S(═O)₂O(R⁰ or H); S(═O)₂—N(R⁰ or H)₂.

The compounds according to the invention are defined by substituents,for example by R¹, R² and R³ (1^(st) generation substituents), which arein turn optionally substituted (2^(nd) generation substituents).Depending on the definition, these substituents of the substituents canthemselves be substituted again (3^(rd) generation substituents). Forexample, if R³═R⁰ where R⁰=aryl (1^(st) generation substituent), thenaryl can itself be substituted, e.g. with NHR⁰, where R⁰═C₁₋₁₀ alkyl(2^(nd) generation substituent). This gives the functional grouparyl-NHC₁₋₁₀ alkyl. C₁₋₁₀ alkyl can then itself be substituted again,for example with Cl (3^(rd) generation substituent). This then gives intotal the functional group aryl-NHC₁₋₁₀ alkyl-Cl.

In a preferred embodiment the 3^(rd) generation substituents cannot,however, be substituted again, i.e. there are then no 4^(th) generationsubstituents.

In another preferred embodiment the 2^(nd) generation substituentscannot be substituted again, i.e. there are then no 3^(rd) generationsubstituents either. In other words, in this embodiment the functionalgroups for R⁰ to R²³ can each optionally be substituted, but the varioussubstituents cannot then themselves be substituted again.

If a radical occurs more than once within a molecule, such as theradical R⁰ for example, then this radical can have different meaningsfor different substituents: for example, if both R¹¹═R⁰ and R¹⁵═R⁰, thenfor R¹¹R⁰ can denote aryl and for R¹⁵R⁰ can denote C₁₋₁₀ alkyl.

In some cases the compounds according to the invention are defined bysubstituents which together with the carbon atom(s) or heteroatom(s)binding them as ring member or ring members form a ring, for example aC₃₋₇ cycloalkyl or a heterocyclyl, each saturated or unsaturated,unsubstituted or mono- or polysubstituted. These ring systems thusformed can optionally be fused to (hetero)aryl, i.e. to an aryl such asphenyl or a heteroaryl such as pyridyl, wherein the (hetero)aryl radicalcan be unsubstituted or mono- or polysubstituted. The ring systems thusformed are preferably fused to an aryl, particularly preferably tophenyl. If the substituents R¹¹ and R¹³, for example, form a cyclohexylring with the carbon atoms binding them, then this cyclohexyl ring canbe fused to phenyl to form tetrahydronaphthyl.

Within the meaning of this invention the term “salt formed with aphysiologically compatible acid” is understood to mean salts of theindividual active ingredient with inorganic or organic acids which arephysiologically—particularly when used in humans and/ormammals—compatible. Hydrochloride is particularly preferred. Examples ofphysiologically compatible acids are: hydrochloric acid, hydrobromicacid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid,oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid,maleic acid, lactic acid, citric acid, glutamic acid, saccharinic acid,monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid,α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/oraspartic acid. Citric acid and hydrochloric acid are particularlypreferred.

Physiologically compatible salts with cations or bases are salts of theindividual compound as anion with at least one, preferably inorganic,cation, which are physiologically—particularly when used in humansand/or mammals—compatible. Particularly preferred are the salts of thealkali and alkaline-earth metals, but also ammonium salts, but inparticular (mono) or (di)sodium, (mono) or (di)potassium, magnesium orcalcium salts.

In a preferred embodiment the substituent R¹ is selected from the groupconsisting of C₁₋₁₀ alkyl, preferably C₁₋₆ alkyl, or C₂₋₁₀ heteroalkyl,each saturated or unsaturated, branched or unbranched, unsubstituted ormono- or polysubstituted; C₃₋₇ cycloalkyl, preferably C₃₋₆ cycloalkyl,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted; aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted; C₁₋₈ alkyl-bridged C₃₋₇ cycloalkyl, preferably C₃₋₆cycloalkyl, each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be branched or unbranched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; C₁₋₈alkyl-bridged heteroaryl, unsubstituted or mono- or polysubstituted,wherein the alkyl chain can be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₁₋₈alkyl-bridged aryl, unsubstituted or mono- or polysubstituted, whereinthe alkyl chain can be unbranched, saturated or unsaturated,unsubstituted;

and the substituent R² is selected from the group consisting of H orC₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted.

In a further preferred embodiment the substituent R¹ is selected fromthe group consisting of C₁₋₁₀ alkyl, saturated or unsaturated, branchedor unbranched, unsubstituted; C₃₋₇ cycloalkyl, saturated or unsaturated,unsubstituted or mono- or polysubstituted; phenyl, thienyl or pyridyl,each unsubstituted or mono- or polysubstituted; C₁₋₄ alkyl-bridged C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be branched or unbranched,saturated or unsaturated, unsubstituted; C₁₋₄ alkyl-bridged thienyl orpyridyl, each unsubstituted or mono- or polysubstituted, wherein thealkyl chain can be branched or unbranched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or C₁₋₄ alkyl-bridged phenyl,unsubstituted or mono- or polysubstituted, wherein the alkyl chain canbe unbranched, saturated or unsaturated, unsubstituted;

and the substituent R² is selected from the group consisting of H orC₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted.

In a further preferred embodiment the substituent R¹ is selected fromthe group consisting of

C₁₋₁₀ alkyl, saturated, branched or unbranched, unsubstituted; or

in accordance with the general formula (Ia) below denotes(CH₂)_(e)-bridged phenyl,

-   -   mono- or disubstituted with R^(16a) and/or R^(16b);        or in accordance with the general formula (Ib) below denotes        (CH₂)_(e)-bridged thienyl,

-   -   mono- or disubstituted with R^(16c) and/or R^(16d);        or in accordance with the general formula (Ic) below denotes        (CH₂)_(e)-bridged pyridyl,

-   -   mono- or disubstituted with R^(16e) and/or R^(16f);    -   wherein just one of the substituents T, U and V stands for N and        the remaining substituents in each case denote CH;        or in accordance with the general formula (Id) below denotes        (CH₂)_(e)-bridged C₃₋₇ cycloalkyl,

-   -   mono- or disubstituted with R^(17a) and/or R^(17b);    -   wherein h denotes 0, 1, 2, 3 or 4, preferably stands for 0;        and the substituent R² stands in each case for H;        wherein e stands in each case for 0, 1, 2, 3 or 4, preferably        for 0;        R^(16a), R^(16b), R^(16c), R^(16d), R^(16e) and R^(16f) are each        mutually independently selected from the group consisting of H,        F, Cl, Br, CN, NH₂, OCF₃, SCF₃, CF₃, C₁₋₈ alkyl or O—C₁₋₈ alkyl,        each saturated or unsaturated, branched or unbranched,        unsubstituted or mono- or polysubstituted; aryl, heteroaryl,        each unsubstituted or mono- or polysubstituted;        R^(17a) and R^(17b) are mutually independently selected from the        group consisting of H, F, Cl, Br, CN, NH₂, OCF₃, SCF₃, CF₃, C₁₋₈        alkyl or O—C₁₋₈ alkyl, each saturated or unsaturated, branched        or unbranched, unsubstituted or mono- or polysubstituted; aryl,        heteroaryl, each unsubstituted or mono- or polysubstituted.        R^(16a) and R^(16b) are preferably mutually independently        selected from the group consisting of H, F, Cl, CH₃, OCH₃ and        CF₃; R^(16a) and R^(16b) particularly preferably each stand for        H.        R^(16c) and R^(16d) are preferably mutually independently        selected from the group consisting of H, F, Cl, CH₃, OCH₃ and        CF₃; R^(16c) and R^(16d) particularly preferably each stand for        H.        R^(16e) and R^(16f) are preferably mutually independently        selected from the group consisting of H, F, Cl, CH₃, OCH₃ and        CF₃; R^(16e) and R^(16f) particularly preferably each stand for        H.        h preferably stands for 2 or 3, particularly preferably for 3.        R^(17a) and R^(17b) are preferably mutually independently        selected from the group consisting of H, F, Cl, Br, CH₃, OCH₃        and CF₃; R^(17a) and R^(17b) particularly preferably each stand        for H.

Compounds having the formulae (1a) and (1b) are most particularlypreferred.

In a further preferred embodiment the substituent R¹ is selected fromthe group consisting of C₁₋₆ alkyl or C₃₋₆ cycloalkyl, each saturated,branched or unbranched, unsubstituted.

In a further preferred embodiment the substituents R³, R⁴, R⁵ and R⁶ aremutually independently selected from the group consisting of H; F; Cl;Br; I; NO₂; CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ orH)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰or H)₂; N(R⁰ or H)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃;SR⁰; S(═O)₂R⁰; S(═O)₂O(R⁰ or H); S(═O)₂—N(R⁰ or H)₂.

The substituents R³, R⁴, R⁵ and R⁶ are preferably mutually independentlyselected from the group consisting of H; F; Cl; Br; I; NO₂; CF₃; CN;NH₂, NH—C₁₋₈ alkyl; N(C₁₋₈ alkyl)₂; NH—C(═O)C₁₋₈ alkyl; NH—C(═O) aryl;NH—C(═O) heteroaryl; C₁₋₈ alkyl; CF₃; CHO; C(═O)C₁₋₈ alkyl; C(═O) aryl;C(═O) heteroaryl; CO₂H; C(═O)O—C₁₋₈ alkyl; C(═O)O aryl; C(═O)Oheteroaryl; CONH₂; C(═O)NH—C₁₋₈ alkyl; C(═O)N(C₁₋₈ alkyl)₂; C(═O)NHaryl; C(═O)N(aryl)₂; C(═O)NH heteroaryl; C(═O)N(heteroaryl)₂;C(═O)N(C₁₋₈ alkyl)(aryl); C(═O)N(C₁₋₈ alkyl)(heteroaryl);C(═O)N(heteroaryl)(aryl); OH; 0-C₁₋₈ alkyl; OCF₃; O—(C₁₋₈ alkyl)-O;O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; O-benzyl; O-aryl; O-heteroaryl;O—C(═O)C₁₋₈-alkyl; O—C(═O)aryl; O—C(═O)heteroaryl; SH; S—C₁₋₈ alkyl;SCF₃; S-benzyl; S-aryl; S-heteroaryl; aryl; heteroaryl; C₃₋₇ cycloalkyl;heterocyclyl or C₁₋₈ alkyl-bridged aryl, heteroaryl, C₃₋₇ cycloalkyl orheterocyclyl.

The substituents R³, R⁴, R⁵ and R⁶ are particularly preferably eachmutually independently selected from the group consisting of H; F; Cl;Br; CN; CF₃; NH₂; OCF₃; SCF₃; C₁₋₈ alkyl; O—C₁₋₈ alkyl; NH(C₁₋₈ alkyl);N(C₁₋₈ alkyl)₂; OH; and SH.

The substituents R³, R⁴, R⁵ and R⁶ are most particularly preferably eachmutually independently selected from the group consisting of H; F; Cl;OCH₃; CH₃; CF₃ and OCF₃.

In particular R³ and R⁵ each stand for H and R⁴ and R⁶ are each mutuallyindependently selected from the group consisting of H; F; OCH₃; CH₃ andCF₃.

In a further preferred embodiment the substituents R⁷, R⁸, R⁹ and R¹⁰are each mutually independently selected from the group consisting of H,C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted.

The substituents R⁷, R⁸, R⁹ and R¹⁰ are preferably mutuallyindependently selected from the group consisting of H or C₁₋₁₀ alkyl,saturated, unbranched, unsubstituted.

The substituents R⁷, R⁸, R⁹ and R¹⁰ are particularly preferably mutuallyindependently selected from the group consisting of H or CH₃.

In a further preferred embodiment the substituent R¹¹ is selected fromthe group consisting of H; F; Cl; Br; CN; C₁₋₁₀ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; phenyl or heteroaryl, each unsubstituted or mono- orpolysubstituted; C₁₋₄ alkyl-bridged phenyl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted or mono- or polysubstituted;

and R¹³ is selected from the group consisting of H; F; Cl; Br; CN; C₁₋₁₀alkyl, saturated or unsaturated, branched or unbranched, unsubstitutedor mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted ormono- or polysubstituted; C₂₋₄ alkyl-bridged phenyl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted or mono- or polysubstituted;or R¹¹ and R¹³ together with the carbon atoms binding them as ringmembers form a C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, optionally fusedto phenyl, unsubstituted or mono- or polysubstituted.

R¹¹ is preferably selected from the group consisting of H; C₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted; phenyl,unsubstituted or mono- or polysubstituted; C₁₋₄ alkyl-bridged phenyl,unsubstituted or mono- or polysubstituted, wherein the alkyl chain canbe branched or unbranched, saturated or unsaturated, unsubstituted ormono- or polysubstituted;

and the radical R¹³ can be selected from the group consisting of H;C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted; phenyl, unsubstituted or mono- or polysubstituted; C₂₋₄alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, whereinthe alkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted or mono- or polysubstituted.

R¹¹ is particularly preferably selected from the group consisting of H;C₁₋₄ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted; phenyl or benzyl, each unsubstituted or mono- orpolysubstituted;

and the radical R¹³ is selected from the group consisting of H; C₁₋₄alkyl, saturated or unsaturated, branched or unbranched, unsubstituted;phenyl, unsubstituted or mono- or polysubstituted.

The radicals R¹¹ and R¹³ are most particularly preferably each mutuallyindependently selected from the group consisting of H and CH₃; inparticular R¹¹ and R¹³ each stand for H.

In a further preferred embodiment R¹² and R¹⁴ are each mutuallyindependently selected from the group consisting of H; C₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted.

R¹² and R¹⁴ are preferably each mutually independently selected from thegroup consisting of H; C₁₋₄ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted.

The radicals R¹² and R¹⁴ are most particularly preferably each mutuallyindependently selected from the group consisting of H and CH₃; inparticular R¹² and R¹⁴ each stand for H.

In a further preferred embodiment the substituent R¹⁵ is selected fromthe group consisting of C₃₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturatedor unsaturated; branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl, saturated or unsaturated,unsubstituted or mono- or polysubstituted; aryl or heteroaryl,unsubstituted or mono- or polysubstituted; C₁₋₈ alkyl-bridged C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; C₁₋₈ alkyl-bridged aryl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.

The substituent R¹⁵ is preferably selected from the group consisting ofC₃₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturated or unsaturated;branched or unbranched, unsubstituted or mono- or polysubstituted; C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted; aryl or heteroaryl, unsubstituted or mono- orpolysubstituted; C₁₋₈ alkyl-bridged C₃₋₇ cycloalkyl, saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; C₁₋₈ alkyl-bridgedaryl or heteroaryl, each unsubstituted or mono- or polysubstituted,wherein the alkyl chain can in each case be branched or unbranched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; withthe proviso that if R¹⁵ denotes heteroaryl, the heteroaryl is bound by acarbon atom in the heteroaryl.

The radical R¹⁵ particularly preferably stands for C₃₋₁₀ alkyl,saturated or unsaturated; branched or unbranched, unsubstituted or mono-or polysubstituted; or is selected from the following substructures A, Bor C,

whereinn=0, 1, 2, 3, 4, 5, 6, 7 or 8; particularly preferably stands for 0, 1,2 or 3, in particular denotes 1;m=0, 1, 2 or 3;ring X can contain one or two N atoms as ring member(s);ring Y contains at least 1 heteroatom selected from N, O or S and cancontain up to 3 heteroatoms mutually independently selected from N, O orS; and/or can contain one or two double bonds;R¹⁸ and R¹⁹ mutually independently denote H; F; Cl; Br; I; NO₂; CF₃; CN;R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰; O—(C₁₋₈alkyl)-O; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; N(R⁰ or H)₂; N(R⁰ or H)—C(═O)—R⁰;N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SR⁰; S(═O)₂R⁰; S(═O)₂O(R⁰ or H);S(═O)₂—N(R⁰ or H)₂H;or R¹⁸ and R¹⁹ together with the carbon or nitrogen atoms binding themas ring members form an aryl or heteroaryl fused to the phenyl orheteroaryl ring, each unsubstituted or mono- or polysubstituted; or aC₃₋₇ cycloalkyl or heterocyclyl fused to the phenyl or heteroaryl ring,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted;R²⁰ and R²¹ mutually independently denote H or C₁₋₁₀ alkyl, saturated orunsaturated; branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted;or R²⁰ and R²¹ together with the carbon atoms or heteroatoms bindingthem as ring members form an aryl or heteroaryl fused to ring Y, eachunsubstituted or mono- or polysubstituted;R²² and R²³ mutually independently denote H; or C₁₋₁₀ alkyl, saturatedor unsaturated; branched or unbranched, unsubstituted.

Compounds in which R¹⁵ has the meaning of substructure A areparticularly preferred.

In a further preferred embodiment the radical R¹⁵ is selected from thefollowing substructures A-a, B-a or C-a,

whereinn denotes 0, 1, 2 or 3, particularly preferably stands for 1;m=0, 1, 2 or 3;ring X can contain an N atom as ring member;ring Y contains a heteroatom selected from N, O or S and/or contains oneor two double bonds;R¹⁸ and R¹⁹ mutually independently denote H; F; Cl; Br; I; NO₂; CN; NH₂;C₁₋₁₀ alkyl, saturated or unsaturated; branched or unbranched,unsubstituted; benzyl; CF₃; NH(C₁₋₁₀ alkyl); N(C₁₋₁₀ alkyl)₂; OH;O—C₁₋₁₀ alkyl; OCF₃; O—(C₁₋₁₀ alkyl)-O; O-benzyl; SH; S—C₁₋₁₀ alkyl;SCF₃; S-benzyl; phenyl, unsubstituted or mono- or polysubstituted;or R¹⁸ and R¹⁹ together with the carbon or nitrogen atoms binding themas ring members form a phenyl or heteroaryl fused to the phenyl orheteroaryl ring, each unsubstituted or mono- or polysubstituted;R²⁰ and R²¹ together with the carbon atoms or heteroatoms binding themas ring members form a phenyl fused to ring Y, each unsubstituted ormono- or polysubstituted;or R²⁰ and R²¹ together with the carbon atoms or heteroatoms bindingthem as ring members form an aryl or heteroaryl fused to ring Y, eachunsubstituted or mono- or polysubstituted.R²² and R²³ mutually independently denote H or CH₃, in particular R²²and R²³ each stand for H.

Compounds in which R¹⁵ has the meaning of substructure A-a are mostparticularly preferred, wherein

n denotes 0, 1, 2 or 3, in particular 1;

ring X contains no N atom as ring member;

R¹⁸ and R¹⁹ mutually independently denote H; F; Cl; Br; CN; NH₂; C₁₋₄alkyl; CF₃; OH; O—C₁₋₄ alkyl; OCF₃; or SCF₃; in particular R¹⁸ and R¹⁹mutually independently denote H; F; Cl, CH₃, OCH₃ or CF₃;

or R¹⁸ and R¹⁹ together with the phenyl ring X form an indazolyl,unsubstituted or mono- or polysubstituted; or together with the carbonatoms of the phenyl ring X binding them as ring members form O—CH₂—O; orO—CH₂—CH₂—O.

A further preferred embodiment of the compounds according to theinvention having the general formula (1) has the general formula (2)

whereinR¹ stands for C₁₋₁₀ alkyl, preferably C₁₋₆ alkyl, or C₂₋₁₀ heteroalkyl,each saturated or unsaturated, branched or unbranched, unsubstituted ormono- or polysubstituted; C₃₋₇ cycloalkyl, preferably C₃₋₆ cycloalkyl,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted; phenyl, thienyl or pyridyl, each unsubstituted or mono-or polysubstituted; C₁₋₈ alkyl-bridged C₃₋₇ cycloalkyl, saturated orunsaturated, unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, whereinthe alkyl chain can be branched or unbranched, saturated or unsaturated,unsubstituted; or C₁₋₈ alkyl-bridged thienyl or pyridyl, unsubstitutedor mono- or polysubstituted, wherein the alkyl chain can be branched orunbranched, saturated or unsaturated, unsubstituted or mono- orpolysubstituted;R³, R⁴, R⁵ and R⁶ each mutually independently denote H; F; Cl; Br; I;NO₂; CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH;OR⁰; O—(C₁₋₈ alkyl)-O; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; N(R⁰ or H)₂; N(R⁰ orH)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SW; S(═O)₂R⁰; S(═O)₂O(R⁰or H); S(═O)₂—N(R⁰ or H)₂;R⁷, R⁸, R⁹, R¹⁹ mutually independently stand for H; or C₁₋₄ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted;R¹¹ and R¹³ each independently stand for H; C₁₋₁₀ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted;or R¹¹ and R¹³ together with the carbon atoms binding them as ringmembers form a C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted;R¹⁵ stands for C₃₋₁₀ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; C₃₋₇ cycloalkyl,saturated or unsaturated, unsubstituted or mono- or polysubstituted;aryl or heteroaryl, unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl, saturated or unsaturated, unsubstitutedor mono- or polysubstituted, wherein the alkyl chain can in each case bebranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted; C₁₋₈ alkyl-bridged aryl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.

Compounds having the general formula (1) or (2) are particularlypreferred wherein

R¹ is selected from C₁₋₁₀ alkyl, preferably C₁₋₆ alkyl, C₃₋₇ cycloalkyl,preferably C₃₋₆ cycloalkyl, each branched or unbranched, saturated,unsubstituted; phenyl, unsubstituted or mono- or disubstituted withsubstituents mutually independently selected from the group consistingof F, Cl, CH₃, OCH₃ and CF₃; thienyl, unsubstituted or mono- ordisubstituted with F, Cl, CH₃, OCH₃ or CF₃; pyridyl, unsubstituted ormono- or disubstituted with F, Cl, CH₃, OCH₃ or CF₃; C₁₋₃ alkyl-bridgedphenyl, unsubstituted, wherein the alkyl chain is unbranched, saturatedand unsubstituted;R² is selected from H or CH₃, but preferably denotes H;R³, R⁴, R⁵ and R⁶ each mutually independently denote H; F; Cl; CH₃; OCH₃or CF₃;R⁷, R⁸, R⁹ and R¹⁹ each mutually independently denote H or CH₃;R¹¹, R¹², R¹³ and R¹⁴ each mutually independently denote H or CH₃;R¹⁵ stands for C₁₋₁₀ alkyl, saturated or unsaturated, branched orunbranched; phenyl, unsubstituted or mono- or disubstituted withsubstituents mutually independently selected from the group consistingof F, Cl, CH₃, OCH₃ and CF₃;C₁₋₄ alkyl-bridged phenyl, unsubstituted or mono- or disubstituted withsubstituents mutually independently selected from the group consistingof F, Cl, CH₃, OCH₃, CF₃, —O—CH₂—O—; C₁₋₄ alkyl-bridged naphthyl,thienyl, furanyl, indolyl or pyridyl, each unsubstituted; indazolyl,unsubstituted or monosubstituted with CH₃.

Compounds having the general formula (1) or (2) are most particularlypreferred wherein

R¹ is selected from methyl, prop-2-yl, 2-methyl-prop-2-yl andcyclohexyl; phenyl, unsubstituted; thienyl, unsubstituted; pyridyl,unsubstituted;

R² denotes H;

R³ and R⁵ each denote H;

R⁴ and R⁶ each mutually independently denote H; F; CF₃; CH₃; or OCH₃;

R⁷, R⁸, R⁹ and R¹⁹ each mutually independently denote H or CH₃;

R¹¹, R¹², R¹³ and R¹⁴ stand for H;

R¹⁵ stands for C₁₋₄ alkyl, saturated and unbranched; phenyl,unsubstituted or mono- or disubstituted with substituents mutuallyindependently selected from the group consisting of F, Cl, and OCH₃;benzyl, unsubstituted or mono- or disubstituted with substituentsmutually independently selected from the group consisting of F; Cl; CH₃;OCH₃; CF₃; —O—CH₂—O—; C₂₋₄ alkyl-bridged phenyl, unsubstituted;CH₂-bridged naphthyl, thienyl, furanyl or pyridyl, each unsubstituted;C₂H₄-bridged indolyl, unsubstituted; indazolyl, monosubstituted withCH₃.

Particularly preferred are compounds from the group comprising:

-   1    4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric    acid amide;-   2    4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   3    4-Oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric    acid amide;-   4    4-Oxo-4-[1-(4-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   5    4-(7-Fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3-(trifluoromethyl)benzyl)butyric    acid amide;-   6    4-(5-Fluoro-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   7    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   8    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   9    4-(4-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   10    4-(4,4-Dimethyl-1-phenyl-1,3-dihydroisoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   11    4-(7-Methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   12    4-(5-Methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   13    4-(3-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   14    N-(2-Chlorophenyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   15    N-(2,1,3-Benzothiadiazol-4-yl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   16    N-(1-Methyl-6-indazolyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   17    N-(2-Furylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   18    N-Benzyl-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   19    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-pyridylmethyl)butyric    acid amide;-   20    N-[(4-Methoxyphenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   21    4-Oxo-N-phenethyl-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   22    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-pyridylmethyl)butyric    acid amide;-   23    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(3-phenylpropyl)butyric    acid amide;-   24    N-[2-(1H-Indol-3-yl)ethyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   25    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-methoxyphenyl)-4-oxobutyric    acid amide;-   26    N-(2-Chlorophenyl)-4-(5,7-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   27    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-methyl-6-indazolyl)-4-oxobutyric    acid amide;-   28    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-furylmethyl)-4-oxobutyric    acid amide;-   29    N-Benzyl-4-(5,7-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   30    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyric    acid amide;-   31    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[(4-methoxyphenyl)methyl]-4-oxobutyric    acid amide;-   32    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyric    acid amide;-   33    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(3-phenylpropyl)butyric    acid amide;-   34    N-(4-Methoxyphenyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   35    N-(2-Chlorophenyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   36    N-(1-Methyl-6-indazolyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   37    N-(2-Furylmethyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   38    N-Benzyl-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   39    4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyric    acid amide;-   40    N-[(4-Methoxyphenyl)methyl]-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   41    4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyric    acid amide;-   42    4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(3-phenylpropyl)butyric    acid amide;-   43    N-(4-Methoxyphenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   44    N-(2-Chlorophenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   45    N-(1-Methyl-6-indazolyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   46    N-(2-Furylmethyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   47    N-Benzyl-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   48    4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyric    acid amide;-   49    N-[(4-Methoxyphenyl)methyl]-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric    acid amide;-   50    4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyric    acid amide;-   51    4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(4-pyridylmethyl)butyric    acid amide;-   52    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-thienylmethyl)butyric    acid amide;-   53    N-[(2-Chlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   54    N-[(2,4-Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   55    N-[(3,4-Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   56    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(p-tolylmethyl)butyric    acid amide;-   57    N-(1,3-Benzodioxol-5-ylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   58    N-[(3-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   59    N-[(2-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   60    N-[(4-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   61    N-[(2,5-Difluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   62    N-(1-Naphthylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric    acid amide;-   63    4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyric    acid amide;-   64    4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyric    acid amide;-   65    4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyric    acid amide;-   66    4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-propylbutyric    acid amide;-   67    4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric    acid amide;-   68    4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4-(trifluoromethyl)-phenyl]methyl]butyric    acid amide;-   69    4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)-phenyl]methyl]butyric    acid amide;-   70    4-Oxo-4-(1-(2-tolyl)-6-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric    acid amide;-   71    4-(1-(2-Methyl-prop-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;-   72    4-(1-Cyclohexyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric    acid amide;-   73    4-Oxo-4-(1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)phenyl]methyl]butyric    acid amide;    or the physiologically compatible salts thereof.

The substituted tetrahydroisoquinolinyl-4-oxobutyric acid amidesaccording to the invention and the corresponding acids, bases, salts andsolvates are suitable as pharmaceutical active ingredients in medicinalproducts.

The invention therefore also provides a medicinal product containing atleast one substituted tetrahydroisoquinolinyl-4-oxobutyric acid amideaccording to the invention having the general formula (1), wherein theradicals R¹ to R¹⁵ have the meaning given above, and optionally one ormore pharmaceutically compatible auxiliary substances.

The medicinal products according to the invention optionally contain, inaddition to at least one compound according to the invention, suitableadditives and/or auxiliary substances, including carrier materials,fillers, solvents, diluents, dyes and/or binders, and can beadministered as liquid dosage forms in the form of injection solutions,drops or juices, as semi-solid dosage forms in the form of granules,tablets, pellets, patches, capsules, plasters/spray plasters oraerosols. The choice of auxiliary substances, etc., and the amountthereof to use depend on whether the medicinal product is to beadministered by oral, peroral, parenteral, intravenous, intraperitoneal,intradermal, intramuscular, intranasal, buccal, rectal or local means,for example on the skin, mucous membranes or in the eyes. Preparationsin the form of tablets, pastilles, capsules, granules, drops, juices andsyrups are suitable for oral administration; solutions, suspensions,easily reconstitutable dry preparations and sprays are suitable forparenteral, topical and inhalative administration. Compounds accordingto the invention in a depot formulation, in dissolved form or in aplaster, optionally with addition of agents promoting skin penetration,are suitable preparations for percutaneous administration. Preparationforms suitable for oral or percutaneous administration can deliver thecompounds according to the invention on a delayed release basis. Thecompounds according to the invention can also be used in parenterallong-term depot forms, such as implants or implanted pumps, for example.Other additional active ingredients known to the person skilled in theart can be added in principle to the medicinal products according to theinvention.

These medicinal products according to the invention are suitable forinfluencing KCNQ2/3 channels and exert an agonistic or antagonistic, inparticular an agonistic, action.

The medicinal products according to the invention are preferablysuitable for the treatment of disorders or diseases which are at leastpartly mediated by KCNQ2/3 channels.

The medicinal products according to the invention are preferablysuitable for the treatment of one or more diseases chosen from the groupconsisting of pain, preferably pain chosen from the group consisting ofacute pain, chronic pain, neuropathic pain, muscular pain andinflammatory pain, epilepsy, urinary incontinence, anxiety states,dependency, mania, bipolar disorders, migraine, cognitive diseases,dystonia-associated dyskinesias and/or urinary incontinence.

The medicinal products according to the invention are particularlypreferably suitable for the treatment of pain, most particularlypreferably chronic pain, neuropathic pain, inflammatory pain andmuscular pain.

The medicinal products according to the invention are furtherparticularly preferably suitable for the treatment of epilepsy.

The invention also provides the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the preparation of a medicinal product for thetreatment of disorders or diseases which are at least partly mediated byKCNQ2/3 channels.

Preference is given to the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the preparation of a medicinal product for thetreatment of pain, preferably pain chosen from the group consisting ofacute pain, chronic pain, neuropathic pain, muscular pain andinflammatory pain; epilepsy, urinary incontinence, anxiety states,dependency, mania, bipolar disorders, migraine, cognitive diseases,dystonia-associated dyskinesias and/or urinary incontinence.

Particularly preferred is the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the preparation of a medicinal product for thetreatment of pain, most particularly preferably chronic pain,neuropathic pain, inflammatory pain and muscular pain.

Also particularly preferred is the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the preparation of a medicinal product for thetreatment of epilepsy.

The invention also provides at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of disorders or diseases whichare at least partly mediated by KCNQ2/3 channels.

The invention also provides at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of pain, preferably pain chosenfrom the group consisting of acute pain, chronic pain, neuropathic pain,muscular pain and inflammatory pain; epilepsy, urinary incontinence,anxiety states, dependency, mania, bipolar disorders, migraine,cognitive diseases, dystonia-associated dyskinesias and/or urinaryincontinence.

Particularly preferred is at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of pain, most particularlypreferably chronic pain, neuropathic pain, inflammatory pain andmuscular pain.

Particularly preferred is also at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of epilepsy.

The invention also provides the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of disorders or diseases whichare at least partly mediated by KCNQ2/3 channels.

Preference is given to the use of at least one substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amide according to theinvention and optionally one or more pharmaceutically compatibleauxiliary substances for the treatment of pain, preferably pain chosenfrom the group consisting of acute pain, chronic pain, neuropathic pain,muscular pain and inflammatory pain; epilepsy, urinary incontinence,anxiety states, dependency, mania, bipolar disorders, migraine,cognitive diseases, dystonia-associated dyskinesias and/or urinaryincontinence.

The effectiveness against pain can be demonstrated for example in theBennett or Chung model (Bennett, G. J. and Xie, Y. K., A peripheralmononeuropathy in rat that produces disorders of pain sensation likethose seen in man, Pain 1988, 33(1), 87-107; Kim, S. H. and Chung, J.M., An experimental model for peripheral neuropathy produced bysegmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363).The effectiveness against epilepsy can be demonstrated for example inthe DBA/2 mouse model (De Sarro et al., Naunyn-Schmiedeberg's Arch.Pharmacol. 2001, 363, 330-336).

The substituted tetrahydroisoquinolinyl-4-oxobutyric acid amidesaccording to the invention preferably have an EC₅₀ value of at most 11μM or at most 5 μM, more preferably at most 3 μM or at most 2 μM, evenmore preferably at most 1.5 μM or at most 1 μM, most preferably at most0.8 μM or at most 0.6 μM and in particular at most 0.4 μM or at most 0.2μM. Methods for determining the EC₅₀ value are known to the personskilled in the art. The EC₅₀ value is preferably determined byfluorimetry, particularly preferably by the method described in“Pharmacological experiments”.

The invention also provides methods for preparing the substitutedtetrahydroisoquinolinyl-4-oxobutyric acid amides according to theinvention.

The chemicals and reaction components used in the reactions describedbelow are available commercially or can be produced by conventionalmethods known to the person skilled in the art.

General Preparation Methods

In step 1, amines having the general formula II are reacted withsuccinic anhydrides having the general formula III, in a reactionmedium, preferably selected from the group consisting of acetone,acetonitrile, chloroform, dioxane, dichloromethane, ethanol, ethylacetate, nitrobenzene, methanol and tetrahydrofuran, optionally in thepresence of an inorganic base, preferably potassium carbonate, or anorganic base, preferably selected from the group consisting oftriethylamine, pyridine, dimethylaminopyridine anddiisopropylethylamine, preferably at temperatures of −20° C. to 160° C.,to form carboxylic acids having the general formula V.

In step 2, carboxylic acids having the general formula IV, wherein PGstands for a C₁₋₆ alkyl group, preferably methyl, ethyl, isopropyl ortert-butyl, are reacted with amines having the general formula II by themethod described in step 4 to form compounds having the general formulaVI.

Alternatively in step 2, compounds having the general formula IV,wherein PG stands for a C₁₋₆ alkyl group, preferably methyl, ethyl,isopropyl or tert-butyl, are first activated at the acid function, forexample by conversion into the corresponding acid halide, preferablyacid chloride, or into reactive esters, preferably pentafluorophenolicesters, and then reacted with amines having the general formula II in areaction medium, preferably selected from the group consisting ofdiethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol,dimethyl formamide and dichloromethane, with or without the addition ofat least one organic or inorganic base, for example triethylamine,dimethylaminopyridine, pyridine or diisopropylamine, optionally in thepresence of at least one organic base, preferably selected from thegroup consisting of triethylamine, dimethylaminopyridine, pyridine anddiisopropylamine, or an organic base, at temperatures of preferably −20°C. to 100° C., to form compounds having the general formula VI.

In step 3, carboxylic acid esters having the general formula VI, whereinPG stands for a C₁₋₆ alkyl group, preferably methyl, ethyl, isopropyl ortert-butyl, are cleaved, optionally in a reaction medium, preferablyselected from the group consisting of acetone, acetonitrile, chloroform,dioxane, dichloromethane, ethanol, methanol, tetrahydrofuran and wateror in a mixture of these reaction media, optionally in the presence ofan inorganic base, preferably LiOH or NaOH, or optionally in thepresence of an acid, preferably formic acid, hydrochloric acid ortrifluoroacetic acid, optionally in the presence of triethylsilane,triisopropylsilane or ethanediol, preferably at temperatures of −20° C.to 80° C., to form carboxylic acids having the general formula V.

In step 4, carboxylic acids having the general formula V are reactedwith amines having the general formula VII, in a reaction medium,preferably selected from the group consisting of diethyl ether,tetrahydrofuran, acetonitrile, methanol, ethanol, dimethyl formamide anddichloromethane, optionally in the presence of at least one couplingreagent, preferably selected from the group consisting of1-benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate(BOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI),N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU),0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) and 1-hydroxy-7-azabenzotriazole (HOAt), optionally in thepresence of at least one inorganic base, preferably selected from thegroup consisting of potassium carbonate and caesium carbonate, or anorganic base, preferably selected from the group consisting oftriethylamine, pyridine, dimethylaminopyridine anddiisopropylethylamine, preferably at temperatures of −70° C. to 150° C.,to form compounds having the general formula I.

In step 5, amines having the general formula VII are reacted withsuccinic anhydrides having the general formula III, by the methoddescribed in step 1, to form carboxylic acids having the general formulaXVI.

In step 6, amines having the general formula VII are reacted withcarboxylic acids having the general formula VIII, by the methoddescribed in step 2, to form compounds having the general formula IX.

In step 7, carboxylic acid esters having the general formula IX, whereinPG stands for a C₁₋₆ alkyl group, preferably methyl, ethyl, isopropyl ortert-butyl, are cleaved by the method described in step 3 to formcarboxylic acids having the general formula XVI.

In step 8, amines having the general formula II are reacted withcarboxylic acids having the general formula XVI, by the method describedin step 4, to form compounds having the general formula I.

In step 9, amines having the general formula X are reacted with ketonesor aldehydes (R²═H) having the general formula XI, in a reaction medium,preferably selected from the group consisting of acetonitrile,chloroform, dichloromethane, diethyl ether, ethanol, methanol,tetrahydrofuran, toluene and xylene, optionally in the presence of aninorganic base, preferably potassium carbonate, or an organic base,preferably selected from the group consisting of triethylamine,pyridine, dimethylaminopyridine and diisopropylethylamine, preferably attemperatures of 0° C. to 160° C., to form imines having the generalformula XII.

In step 10, imines having the general formula XII are cyclised,optionally in a reaction medium, preferably selected from the groupconsisting of benzene, ethanol, methanol, toluene, water and xylene,with the addition of an acid, preferably selected from the groupconsisting of hydrochloric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid, preferably at temperatures of 0° C. to160° C., to form compounds having the general formula II.

In step 11, amines having the general formula X are reacted withcarboxylic acids having the general formula XIII, by the methoddescribed in step 4, to form amides having the general formula XIV.

In step 12, amides having the general formula XIV are cyclised in areaction medium, preferably selected from the group consisting ofbenzene, chloroform, toluene or xylene, in the presence of a suitablecyclisation reagent, preferably phosphoryl trichloride or phosphoruspentachloride, optionally with the addition of phosphorus pentoxide,preferably at temperatures of 20° C. to 150° C., to form compoundshaving the general formula XV.

In step 13, compounds having the general formula XIV are reduced in areaction medium, preferably selected from the group consisting ofdiethyl ether, ethanol, acetic acid, methanol and tetrahydrofuran, inthe presence of a suitable reducing agent, preferably selected from thegroup consisting of sodium boron hydride, sodium cyanoboron hydride,lithium aluminium hydride or hydrogen, optionally with the addition of acatalyst, preferably selected from the group consisting of palladium,platinum, platinum oxide or Raney nickel, optionally with the additionof an organic base selected from the group consisting of ammonia,triethylamine and diisopropyl ethylamine, preferably at temperatures of−20° C. to 100° C., to form compounds having the general formula II′(R²═H).

DESCRIPTION OF THE EXAMPLE SYNTHESES Abbreviations

-   AcOH acetic acid-   aq. aqueous-   brine saturated aqueous NaCl solution-   d days-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine-   EDC N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride-   EE ethyl acetate-   ether diethyl ether-   sat. saturated-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOAt 7-aza-1-hydroxy-1H-benzotriazole-   HOBt 1-hydroxy-1H-benzotriazole-   sol. solution-   m/z mass-to-charge ratio-   M molar-   MeCN acetonitrile-   MeOH methanol-   max. maximum-   min minutes-   MS mass spectrometry-   N/A not available-   NEt₃ triethylamine-   PS carbodiimide a polymer-bound carbodiimide having the following    structure:

-   -   Loading: 0.9-1.4 mmol/g    -   Particle size: 75-150 μm

-   PPA polyphosphoric acid

-   RG retigabine

-   RT room temperature 23±7° C.

-   SC column chromatography on silica gel

-   THF tetrahydrofuran

-   vv ratio by volume

All starting materials not explicitly described were either availablecommercially (suppliers can be found for example in the Symyx® AvailableChemicals Database from MDL, San Ramon, US), or their synthesis isalready accurately described in the specialist literature (experimentalprocedures can be found for example in the Reaxys® database fromElsevier, Amsterdam, NL), or can be prepared by methods known to theperson skilled in the art.

Silica gel 60 (0.040-0.063 mm) was used as the stationary phase forcolumn chromatography (SC).

The analytical characterisation of all intermediates and examplecompounds was performed by means of ¹H-NMR spectroscopy. An analysis bymass spectrometry (MS, m/z stated for [M+H]⁺) was also performed for allexample compounds and selected intermediates.

Synthesis of Intermediates Synthesis of intermediate VVV01:4-Oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid

A solution of 15.0 g (85.6 mmol) of(3-(trifluoromethyl)phenyl)methylamine in ether (40 ml) was addeddropwise to a suspension of 7.5 g (85.6 mmol) of succinic anhydride inether (450 ml) within 30 min. The mixture was then stirred for 72 h atroom temperature. The deposit obtained was filtered and dried. Aftercolumn chromatography (EE/MeOH 1:1) of the residue, 10.4 g (37.8 mmol,44%) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid wereobtained.

Synthesis of intermediate VVV04:4-(7-Fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acida) Synthesis of N-(4-fluorophenethyl)benzamide

1.5 g (10.8 mmol) of HOAt were added to a solution of 15.0 g (108.0mmol) of 4-fluorophenethylamine and 13.2 g (108.0 mmol) of benzoic acidin DCM and the mixture was then cooled to 0° C. 22.8 g (119.0 mmol) ofEDC were then added at this temperature and the mixture was then stirredfor 16 h at RT. The reaction solution was then washed successively witha 1M aqueous hydrochloric acid (2×300 ml), a 2M aqueous NaOH solution(300 ml) and brine (200 ml). The organic phase was dried over Na₂SO₄,filtered and concentrated to small volume under vacuum. 20.5 g (84.2mmol, 78%) of N-(4-fluorophenethyl)benzamide were obtained as theresidue.

b) Synthesis of 7-fluoro-1-phenyl-3,4-dihydroisoquinoline

A mixture of 12.5 g (51.4 mmol) of N-(4-fluorophenethyl)benzamide andpolyphosphoric acid (150 ml) was heated at 150° C. for 5 days. Then thehot solution was poured into water and the reaction was quenched by theaddition of NaHCO₃. It was extracted with DCM (3×300 ml). The combinedorganic phases were washed with brine (300 ml), dried over Na₂SO₄,filtered and concentrated to small volume under vacuum. 3.2 g of thecrude product 7-fluoro-1-phenyl-3,4-dihydroisoquinoline were obtained asthe residue, which was reacted further with no additional purification.

c) Synthesis of 7-fluoro-1-phenyl-1,2,3,4-tetrahydroisoquinoline

0.65 g (17.1 mmol) of NaBH₄ were added in portions to a solution of 3.2g (max. 14.2 mmol) of the crude product7-fluoro-1-phenyl-3,4-dihydroisoquinoline in EtOH (80 ml) and themixture was then stirred for 16 h at RT. Then the mixture wasconcentrated to small volume under vacuum and the residue was taken upwith DCM (200 ml). It was washed with water and the aqueous phase wasextracted with DCM (2×150 ml). The combined organic phases were washedwith brine, dried over Na₂SO₄, filtered and concentrated to small volumeunder vacuum. 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroisoquinoline wasobtained as the crude product, which was reacted further with noadditional purification.

d) Synthesis of4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid

5.0 g (49.7 mmol) of succinic anhydride and 4.0 ml (28.4 mmol) of NEt₃were added in succession to a solution of the crude product7-fluoro-1-phenyl-1,2,3,4-tetrahydroisoquinoline (max. 14.2 mmol) inMeCN (200 ml) and the mixture was stirred for 16 h at RT. It was thenconcentrated to small volume under vacuum and the residue was taken upwith a saturated aqueous NaHCO₃ solution (300 ml). It was extracted withDCM (2×200 ml). The combined organic phases were washed with a 1Maqueous hydrochloric acid (200 ml), dried over Na₂SO₄, filtered andconcentrated to small volume under vacuum. Column chromatography(heptane/EE 1:1+1% AcOH) of the residue produced 1.72 g (5.3 mmol, 10%over 3 stages) of4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid.

Synthesis of intermediate VVV06:4-(7-Methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acida) Synthesis of N-(4-methoxyphenethyl)benzamide

The synthesis of 4.98 g (19.5 mmol, 98%) ofN-(4-methoxyphenethyl)benzamide took place by the method described forintermediate VVV04 in a).

b) Synthesis of 7-methoxy-1-phenyl-3,4-dihydroisoquinoline

A mixture of 4.0 g (15.7 mmol) of N-(4-methoxyphenethyl)benzamide and21.1 ml (227.0 mmol) of POCl₃ in MeCN (120 ml) was refluxed for 16 h.The mixture was then concentrated to small volume under vacuum, taken upwith MeOH and concentrated to small volume under vacuum again. This stepwas repeated three times. 24.65 g of the crude product7-methoxy-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue,which was reacted further with no additional purification.

c) Synthesis of 7-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline

24.65 g (max. 15.7 mmol) of the crude product from b) were reacted bythe method described for intermediate VVV04 in c) to form7-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline. The 6.81 g of crudeproduct that were obtained were used with no further purification.

d) Synthesis of4-(7-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid

6.81 g of the crude product from c) were reacted by the method describedfor intermediate VVV04 in d) to form4-(7-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyricacid. 2.2 g (6.5 mmol, 41% over 3 stages) of4-(7-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acidwere obtained.

Synthesis of intermediate VVV09:4-(7-Methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acida) Synthesis of 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline

A mixture of 12.0 g (89 mmol) of 2-p-tolylethylamine and 11.21 ml (111mmol) of benzaldehyde in PPA (300 g) was heated at 100° C. for 5 days.After cooling to RT it was poured into a saturated aqueous K₂CO₃solution (1200 ml). Following the addition of DCM (300 ml) it wasstirred for 50 min at RT. Then the phases were separated and the aqueousphase was extracted with DCM (2×500 ml). The organic phases werecombined, dried over Na₂SO₄, filtered and concentrated to small volumeunder vacuum. 16.3 g of 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinewere obtained as the crude product, which was reacted further with noadditional purification.

b) Synthesis of4-(7-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid

25.5 g (255 mmol) of succinic anhydride and 20.3 ml (146 mmol) of NEt₃were added in succession to a solution of 16.3 g of the crude product7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline from a) in MeCN (300ml) and the mixture was stirred for 16 h at RT. It was then concentratedto small volume under vacuum. The residue was taken up with DCM (400ml). It was then washed with a saturated aqueous NaHCO₃ solution. Theaqueous phase was extracted with DCM (2×400 ml). The collected organicphases were washed with 1N aqueous hydrochloric acid (400 ml) and withbrine, dried over Na₂SO₄, filtered and concentrated to small volumeunder vacuum. Column chromatography (gradient heptane/EE 1:1heptane/EE/AcOH 2:2:1) of the residue and subsequent crystallisation ofthe residue from EE produced 6.79 g (21 mmol, 24% over 2 stages) of4-(7-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid.

Synthesis of intermediate VVV12:4-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline

4 Å molecular sieve (10 g) was added to a solution of 1.06 g (10.0 mmol)of benzaldehyde and 1.35 g (10.0 mmol) of 2-phenylpropylamine in toluene(45 ml) and the mixture was refluxed for 4 h. After cooling to RT themixture was filtered through diatomaceous earth and the filtrate wasconcentrated to small volume under vacuum. The residue was dissolved inTFA (90 ml) and the solution was heated at 120° C. for 20 h. Then it wasconcentrated to small volume under vacuum and made alkaline with a 2Naqueous NaOH solution. It was then extracted with EE. The organic phasewas dried over Na₂SO₄, filtered and concentrated to small volume undervacuum. Column chromatography (hexane/EE 7:3) of the residue produced1.74 g (7.8 mmol, 78%) of4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline.

Synthesis of intermediate VVV14:4,4-Dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline a) Synthesis ofN-(2-methyl-2-phenylpropyl)benzamide

4.0 ml (30 mmol) of NEt₃ and 4.22 g (30 mmol) of benzoylchloride wereadded in succession at 0° C. to a solution of 1.86 g (10.0 mmol) of2-methyl-2-phenylpropylamine hydrochloride in DCM (30 ml) and themixture was stirred for 1 h at RT. It was then diluted with DCM andwashed with a 10% aqueous hydrochloric acid, a saturated aqueous Na₂CO₃solution and brine. The organic phase was dried over Na₂SO₄, filteredand concentrated to small volume under vacuum. 2.48 g (9.8 mmol, 98%) ofN-(2-methyl-2-phenylpropyl)benzamide were obtained as the residue, whichwas reacted further with no additional purification.

b) Synthesis of 4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline

1.42 g (10.0 mmol) of P₂O₅ and POCl₃ (4 ml) were added to a solution of1.27 g (5.0 mmol) of N-(2-methyl-2-phenylpropyl)benzamide in xylene (20ml) and the mixture was heated at 150° C. for 3 h. After cooling to RTthe mixture was concentrated to small volume under vacuum. The residuewas made alkaline with a 20% aqueous NaOH solution. It was thenextracted with EE and the organic phase was dried over Na₂SO₄, filteredand concentrated to small volume under vacuum. 634 mg (2.7 mmol) of4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline were obtained as theresidue, which was reacted further with no additional purification.

c) Synthesis of 4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline

A solution of 471 mg (2.0 mmol) of4,4-dimethyl-1-phenyl-3,4-dihydroisoquinoline in MeOH (6 ml) was cooledto 0° C. and 151 mg (4.0 mmol) of NaBH₄ were added in portions. Afterstirring for 3 h at RT a saturated aqueous NH₄Cl solution was added.Then most of the methanol was removed under vacuum and the residue wasextracted with EE. The organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated to small volume under vacuum. 19 mg(0.08 mmol, 4%) of 4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinewere obtained as the residue, which was reacted further with noadditional purification.

Synthesis of Further Intermediates

The synthesis of further intermediates took place by the methods alreadydescribed. Table 1 shows which compound was prepared by which method.The starting materials and reagents used in each case are apparent tothe person skilled in the art.

TABLE 1 Preparation Inter- analogous to Yield mediate Chemical nameintermediate [%] VVV02 4-Oxo-4-(2- VVV01 28(trifluoromethyl)benzylamino)butyric acid VVV03 4-Oxo-4-(4- VVV01 30(trifluoromethyl)benzylamino)butyric acid VVV054-(5-Fluoro-1-phenyl-3,4- VVV04 12 dihydroisoquinolin-2(1H)-yl)- (4stages) 4-oxobutyric acid VVV07 4-(5-Methoxy-1-phenyl-3,4- VVV06 51dihydroisoquinolin-2(1H)-yl)- (4 stages) 4-oxobutyric acid VVV084-(1-Phenyl-3,4- VVV04 d) 58 dihydroisoquinolin-2(1H)-yl)- 4-oxobutyricacid VVV10 4-(5-Methyl-1-phenyl-3,4- VVV09 25dihydroisoquinolin-2(1H)-yl)- (2 stages) 4-oxobutyric acid VVV114-(5,7-Dimethyl-1-phenyl-3,4- VVV09 30 dihydroisoquinolin-2(1H)-yl)- (2stages) 4-oxobutyric acid VVV13 3-Methyl-1-phenyl-1,2,3,4- VVV12 39tetrahydroisoquinoline VVV15 4-(1-(2-Tolyl)-3,4- VVV09 75dihydroisoquinolin- (2 stages) 2(1H)-yl)-4-oxobutyric acid VVV164-(1-Cyclohexyl-3,4- VVV09 58 dihydroisoquinolin- (2 stages)2(1H)-yl)-4-oxobutyric acid VVV17 4-(1-(2-Methyl-prop-2-yl)-3,4- VVV0998 dihydroisoquinolin-2(1H)-yl)- (2 stages) 4-oxobutyric acid VVV184-(1-(2-Fluorophenyl)-3,4- VVV09 84 dihydroisoquinolin-2(1H)-yl)- (2stages) 4-oxobutyric acid

Synthesis of the Example Compounds Synthesis of example compound 1:4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide

1.98 g (˜2.0 mmol) of PS carbodiimide resin were added to a solution of209 mg (1.0 mmol) of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 275 mg(1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid(intermediate VVV01) in a mixture of DCM and DMF (82 ml, 40:1 vv) andthe mixture was shaken for 16 h at RT. Then the resin was filtered offand it was washed with DCM and MeOH. The filtrate was concentrated tosmall volume under vacuum. Column chromatography (DCM/EtOH 40:1) of theresidue produced 287 mg (0.6 mmol, 62%) of4-oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide. MS: m/z 467.2 [M+H]⁺.

Synthesis of example compound 3:4-Oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide

236 mg (1.1 mmol) of 1-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline,380 mg (1.0 mmol) of HATU and 263 μl (1.9 mmol) of NEt₃ were added insuccession to a solution of 275 mg (1.0 mmol) of4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediateVVV01) in THF (8 ml) and the mixture was then stirred for 24 h at RT.Then it was diluted with EE (30 ml) and washed twice with a 4M aqueousNH₄Cl solution and with a 1M aqueous NaHCO₃ solution. The organic phasewas dried over MgSO₄, filtered and concentrated to small volume undervacuum. Column chromatography (EE) of the residue produced 410 mg (0.87mmol, 87%) of4-oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide. MS: m/z 473.1 [M+H]⁺.

Synthesis of example compound 5:4-(7-Fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3-(trifluoromethyl)benzyl)butyricacid amide

A solution of 200 mg (0.61 mmol) of4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid(intermediate VVV04) and 88.0 μl (0.61 mmol) of 3-trifluoromethylbenzylamine in DCM (15 ml) was cooled to 0° C. and then 8.3 mg (0.06mmol) of HOAt and 129 mg (0.67 mmol) of EDC were added in succession.The mixture was then stirred for 16 h at room temperature. The reactionsolution was poured into water (75 ml) and extracted with DCM (2×75 ml).The combined organic phases were washed with a 1M aqueous NaOH solution(100 ml) and brine, dried over Na₂SO₄, filtered and concentrated tosmall volume under vacuum. Column chromatography (heptane/EE 1:1+2% 7NNH₃ in MeOH) of the residue produced 240 mg (0.50 mmol, 81%) of4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3-(trifluoromethyl)benzyl)butyricacid amide. MS: m/z 485.2 [M+H]⁺.

Synthesis of example compound 9:4-(4-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide

384 mg (2.0 mmol) of EDC, 306 μl (1.8 mmol) of DIPEA and 135 mg (1.0mmol) of HOBt were added to a solution of 275 mg (1.0 mmol) of4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediateVVV01) in DCM (13 ml) and the mixture was stirred for 5 min at RT. Then268 mg (1.2 mmol) of 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinewere added and the mixture was stirred for a further 2 h at RT. It wasthen diluted with DCM and washed successively with a 10% aqueoushydrochloric acid, a saturated aqueous Na₂CO₃ solution, a saturatedaqueous NH₄Cl solution and brine. The organic phase was dried overNa₂SO₄, filtered and concentrated to small volume under vacuum. Columnchromatography (hexane/EE 7:3) of the residue produced 346 mg (0.72mmol, 72%) of4-(4-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide. MS: m/z 481.2 [M+H]⁺.

Automated Synthesis of Example Compounds 14-73

The correspondingly substituted4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-butyric acid derivative (100μmol, 0.05 M in DCM (2 ml) or in a DCM/THF blend (3:1 vv, 2 ml)) wasplaced in a dry threaded glass jar sealed with a septum cover at RT andcarbonyl diimidazole (105 μmol, 0.05 M in DCM (1 ml)) was added. After areaction time of 1 h at RT the corresponding amine derivative (100 μmol,0.1 M in DCM (1 ml)) was added at RT. After stirring for 16 h at RT themixture was hydrolysed with water (3 ml), the reaction vessel drainedand rinsed with DCM (2.5 ml). The phases were separated and the organicphase was washed again with water (3 ml) and then with brine (3 ml). Thesolvent was removed under vacuum and the products purified by HPLC.Analysis was performed by mass spectroscopy and the specified m/z (M+Hrfound for all compounds.

Synthesis of Further Example Compounds

The synthesis of further example compounds took place by the methodsalready described. Table 2 shows which compound was prepared by whichmethod. The starting materials and reagents used in each case areapparent to the person skilled in the art.

TABLE 2 Preparation analogous Yield MS m/z Example Chemical name toexample [%] [M + H]⁺ 2 4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2- 1 38405.2 yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide4 4-Oxo-4-[1-(4-pyridyl)-3,4-dihydro-1H- 3 42 468.2isoquinolin-2-yl]-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acidamide 6 4-(5-Fluoro-1-phenyl-3,4-dihydro-1H- 5 92 485.2isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyricacid amide 7 4-Oxo-4-(1-phenyl-3,4-dihydro-1H- 3 55 467.2isoquinolin-2-yl)-N-[[2- (trifluoromethyl)phenyl]methyl]butyric acidamide 8 4-Oxo-4-(1-phenyl-3,4-dihydro-1H- 3 68 467.2isoquinolin-2-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]butyric acidamide 10 4-(4,4-Dimethyl-1-phenyl-1,3- 9 49 495.2dihydroisoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide 114-(7-Methoxy-1-phenyl-3,4-dihydro-1H- 5 18 497.2isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyricacid amide 12 4-(5-Methoxy-1-phenyl-3,4-dihydro-1H- 5 14 497.2isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyricacid amide 13 4-(3-Methyl-1-phenyl-3,4-dihydro-1H- 5 52 481.2isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyricacid amide 14 N-(2-Chlorophenyl)-4-oxo-4-(1-phenyl-3,4- 14-73 N/A 419.1dihydro-1H-isoquinolin-2-yl)butyric acid amide 15N-(2,1,3-Benzothiadiazol-4-yl)-4-oxo-4-(1- 14-73 N/A 443.1phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 16N-(1-Methyl-6-indazolyl)-4-oxo-4-(1-phenyl-3,4- 14-73 N/A 439.2dihydro-1H-isoquinolin-2-yl)butyric acid amide 17N-(2-Furylmethyl)-4-oxo-4-(1-phenyl-3,4- 14-73 N/A 389.2dihydro-1H-isoquinolin-2-yl)butyric acid amide 18N-Benzyl-4-oxo-4-(1-phenyl-3,4-dihydro- 14-73 N/A 399.21H-isoquinolin-2-yl)butyric acid amide 194-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 400.2isoquinolin-2-yl)-N-(2- pyridylmethyl)butyric acid amide 20N-[(4-Methoxyphenyl)methyl]-4-oxo-4-(1- 14-73 N/A 429.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 214-Oxo-N-phenethyl-4-(1-phenyl-3,4- 14-73 N/A 413.2dihydro-1H-isoquinolin-2-yl)butyric acid amide 224-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 400.2isoquinolin-2-yl)-N-(4-pyridylmethyl)butyric acid amide 234-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 427.2isoquinolin-2-yl)-N-(3-phenylpropyl)butyric acid amide 24N-[2-(1H-Indol-3-yl)ethyl]-4-oxo-4-(1- 14-73 N/A 452.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 254-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 443.2isoquinolin-2-yl)-N-(4-methoxyphenyl)-4- oxobutyric acid amide 26N-(2-Chlorophenyl)-4-(5,7-dimethyl-1- 14-73 N/A 447.2phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 274-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 467.2isoquinolin-2-yl)-N-(1-methyl-6-indazolyl)- 4-oxobutyric acid amide 284-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 417.2isoquinolin-2-yl)-N-(2-furylmethyl)-4- oxobutyric acid amide 29N-Benzyl-4-(5,7-dimethyl-1-phenyl-3,4- 14-73 N/A 427.2dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide 304-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 428.2isoquinolin-2-yl)-4-oxo-N-(2- pyridylmethyl)butyric acid amide 314-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 457.2isoquinolin-2-yl)-N-[(4- methoxyphenyl)methyl]-4-oxobutyric acid amide32 4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 441.2isoquinolin-2-yl)-4-oxo-N-phenethylbutyric acid amide 334-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 455.3isoquinolin-2-yl)-4-oxo-N-(3- phenylpropyl)butyric acid amide 34N-(4-Methoxyphenyl)-4-(5-methyl-1- 14-73 N/A 429.2phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 35N-(2-Chlorophenyl)-4-(5-methyl-1-phenyl- 14-73 N/A 433.23,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 36N-(1-Methyl-6-indazolyl)-4-(5-methyl-1- 14-73 N/A 453.2phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 37N-(2-Furylmethyl)-4-(5-methyl-1-phenyl- 14-73 N/A 403.23,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 38N-Benzyl-4-(5-methyl-1-phenyl-3,4-dihydro- 14-73 N/A 413.21H-isoquinolin-2-yl)-4-oxobutyric acid amide 394-(5-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 414.2isoquinolin-2-yl)-4-oxo-N-(2- pyridylmethyl)butyric acid amide 40N-[(4-Methoxyphenyl)methyl]-4-(5-methyl- 14-73 N/A 443.21-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxobutyric acid amide 414-(5-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 427.2isoquinolin-2-yl)-4-oxo-N-phenethylbutyric acid amide 424-(5-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 441.2isoquinolin-2-yl)-4-oxo-N-(3- phenylpropyl)butyric acid amide 43N-(4-Methoxyphenyl)-4-(7-methyl-1- 14-73 N/A 429.2phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 44N-(2-Chlorophenyl)-4-(7-methyl-1-phenyl-3,4- 14-73 N/A 433.2dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide 45N-(1-Methyl-6-indazolyl)-4-(7-methyl-1- 14-73 N/A 453.2phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 46N-(2-Furylmethyl)-4-(7-methyl-1-phenyl- 14-73 N/A 403.23,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide 47N-Benzyl-4-(7-methyl-1-phenyl-3,4-dihydro- 14-73 N/A 413.21H-isoquinolin-2-yl)-4-oxobutyric acid amide 484-(7-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 414.2isoquinolin-2-yl)-4-oxo-N-(2- pyridylmethyl)butyric acid amide 49N-[(4-Methoxyphenyl)methyl]-4-(7-methyl- 14-73 N/A 443.21-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxobutyric acid amide 504-(7-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 427.2isoquinolin-2-yl)-4-oxo-N-phenethylbutyric acid amide 514-(7-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 414.2isoquinolin-2-yl)-4-oxo-N-(4- pyridylmethyl)butyric acid amide 524-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 405.2isoquinolin-2-yl)-N-(2-thienylmethyl)butyric acid amide 53N-[(2-Chlorophenyl)methyl]-4-oxo-4-(1- 14-73 N/A 433.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 54N-[(2,4-Dichlorophenyl)methyl]-4-oxo-4- 14-73 N/A 467.1(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 55N-[(3,4-Dichlorophenyl)methyl]-4-oxo-4- 14-73 N/A 467.1(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 564-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 413.2isoquinolin-2-yl)-N-(p-tolylmethyl)butyric acid amide 57N-(1,3-Benzodioxol-5-ylmethyl)-4-oxo-4- 14-73 N/A 443.2(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 58N-[(3-Fluorophenyl)methyl]-4-oxo-4-(1- 14-73 N/A 417.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 59N-[(2-Fluorophenyl)methyl]-4-oxo-4-(1- 14-73 N/A 417.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 60N-[(4-Fluorophenyl)methyl]-4-oxo-4-(1- 14-73 N/A 417.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 61N-[(2,5-Difluorophenyl)methyl]-4-oxo-4-(1- 14-73 N/A 435.2phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide 62N-(1-Naphthylmethyl)-4-oxo-4-(1-phenyl-3,4- 14-73 N/A 449.2dihydro-1H-isoquinolin-2-yl)butyric acid amide 634-(7-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 365.2isoquinolin-2-yl)-4-oxo-N-propylbutyric acid amide 644-(5-Methyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 365.2isoquinolin-2-yl)-4-oxo-N-propylbutyric acid amide 654-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- 14-73 N/A 379.2isoquinolin-2-yl)-4-oxo-N-propylbutyric acid amide 664-Oxo-4-(1-phenyl-3,4-dihydro-1H- 14-73 N/A 351.2isoquinolin-2-yl)-N-propylbutyric acid amide 674-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H- 14-73 54 481.2isoquinolin-2-yl)-N-[[3-(trifluoromethyl)- phenyl]methyl]butyric acidamide 68 4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H- 14-73 51 481.2isoquinolin-2-yl)-N-[[4-(trifluoromethyl)- phenyl]methyl]butyric acidamide 69 4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H- 14-73 59 481.2isoquinolin-2-yl)-N-[[2-(trifluoromethyl)- phenyl]methyl]butyric acidamide 70 4-Oxo-4-(1-(2-tolyl)-6-methyl-3,4-dihydro- 14-73 N/A 495.21H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)- phenyl]methyl]butyric acidamide 71 4-(1-(2-Methyl-prop-2-yl)-3,4-dihydro-1H- 14-73 N/A 447.2isoquinolin-2-yl)-4-oxo-N-[[3- trifluoromethyl)phenyl]methyl]butyricacid amide 72 4-(1-Cyclohexyl-3,4-dihydro-1H- 14-73 N/A 473.2isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyricacid amide 73 4-Oxo-4-(1-(2-fluorophenyl)-3,4-dihydro- 14-73 N/A 485.21H-isoquinolin-2-yl)-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acidamidePharmacological ExperimentsFluorescence Assay Using a Voltage-Sensitive Dye

Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherentlyat 37° C., 5% CO₂ and 95% humidity in cell culture bottles (e.g. 80 cm²TC flasks, Nunc) with DMEM-high glucose (Sigma Aldrich, D7777) including10% FCS (PAN Biotech, e.g. 3302-P270521) or alternatively MEM AlphaMedium (1×, liquid, Invitrogen, #22571), 10% foetal calf serum (FCS)(Invitrogen, #10270-106, heat-inactivated) and the necessary selectionantibiotics.

Before being sown out for the measurements, the cells are washed with a1×DPBS buffer without Ca²⁺/Mg²⁺ (e.g. Invitrogen, #14190-094) anddetached from the bottom of the culture vessel by means of Accutase (PAALaboratories, #L11-007) (incubation with Accutase for 15 min at 37° C.).The cell count then present is determined using a CASY™ cell counter(TCC model, Scharfe System) in order subsequently to apply 20,000 to30,000 cells/well/100 μl of the described nutrient medium, depending ondensity optimisation for the individual cell line, to 96-well measuringplates of the Corning™ CeIIBIND™ type (flat clear-bottom blackpolystyrene microplates, #3340).

Incubation is then carried out for one hour at room temperature, withoutgassing or adjusting the humidity, followed by incubation for 24 hoursat 37° C., 5% CO₂ and 95% humidity.

The voltage-sensitive fluorescent dye from the Membrane Potential AssayKit (Red™ bulk format part R8123 for FLIPR, MDS AnalyticalTechnologies™) is prepared by dissolving the contents of a vessel ofMembrane Potential Assay Kit Red Component A in 200 ml of extracellularbuffer (ES buffer, 120 mM NaCl, 1 mM KCl, 10 mM HEPES, 2 mM CaCl₂, 2 mMMgCl₂, 10 mM glucose; pH 7.4). After removal of the nutrient medium, thecells are washed with 200 μl of ES buffer, then covered with a layer of100 μl of the dye solution prepared above and incubated for 45 min atroom temperature with exclusion of light.

The fluorescence measurements are carried out with a BMG LabtechFLUOstar™ BMG Labtech NOVOstar™ or BMG Labtech POLARstar™ instrument(525 nm excitation, 560 nm emission, bottom-read mode). After incubationof the dye, 50 μl of the substances to be tested in the desiredconcentrations, or 50 μl of ES buffer for control purposes, areintroduced into separate cavities of the measuring plate and incubatedfor 30 min at room temperature whilst being shielded from light. Thefluorescence intensity of the dye is then measured for 5 min and thefluorescence value F₁ of each well is thus determined at a given,constant time. 15 μl of a 100 mM KCl solution (final concentration 92mM) are then added to each well. The change in fluorescence issubsequently measured until all relevant measured values have beenobtained (mainly 5-30 min). At a given time after KCl application, afluorescence value F₂ is determined, in this case at the time of thefluorescence peak.

For calculation, the fluorescence intensity F₂ is compared with thefluorescence intensity F₁, and the agonistic activity of the targetcompound on the potassium channel is determined therefrom. F₂ and F₁ arecalculated as follows:

${( \frac{F_{2} - F_{1}}{F_{1}} ) \times 100} = {\frac{\Delta\; F}{F}(\%)}$

In order to determine whether a substance has an agonistic activity,

$\frac{\Delta\; F}{F},$for example, can be compared with

$( \frac{\Delta\; F}{F} )_{K}$of control cells.

$( \frac{\Delta\; F}{F} )_{K}$is determined by adding to the reaction batch only the buffer solutioninstead of the substance to be tested, determining the value F_(1K) ofthe fluorescence intensity, adding the potassium ions as described aboveand measuring a value F_(2K) of the fluorescence intensity. Then F_(2K)and F_(1K) are calculated as follows:

${{( \frac{F_{2K} - F_{1K}}{F_{1K}} ) \times 100} = {( \frac{\Delta\; F}{F} )_{K}(\%)}}\;$

A substance has an agonistic activity on the potassium channel if

$\frac{\Delta\; F}{F}$is greater than

$ {( \frac{\Delta\; F}{F} )_{K}\text{:}\frac{\Delta\; F}{F}} \rangle( \frac{\Delta\; F}{F} )_{K}$

Independently of the comparison of

${\frac{\Delta\; F}{F}\mspace{14mu}{with}\mspace{14mu}( \frac{\Delta\; F}{F} )_{K}},$it is also possible to conclude that a target compound has an agonisticactivity if an increase in

$\frac{\Delta\; F}{F}$is to be observed as the dosage of the target compound increases.

Calculations of EC₅₀ and IC₅₀ values are carried out with the aid ofPrism v4.0 software (GraphPad Software™).

Voltage-Clamp Measurements

In order to confirm a KCNQ2/3 agonistic action of the substanceselectrophysiologically, patch-clamp measurements (Hamill O P, Marty A,Neher E, Sakmann B, Sigworth F J: Improved patch-clamp techniques forhigh-resolution current recording from cells and cell-free membranepatches, Pfluger's Arch. 1981 August; 391(2):85-100) were performed involtage-clamp mode on a stably transfected hKCNQ2/3 CHO-K1 cell line.After formation of the gigaseal the cells were first clamped at aholding potential of −60 mV. Depolarising voltage jumps up to apotential of +20 mV were then applied (increment: 20 mV, duration: 1second) in order to confirm the functional expression of KCNQ2/3-typicalcurrents. The substances were tested at a potential of −40 mV. First ofall the current increase induced by retigabine (10 μM) at −40 mV wasrecorded on each cell as a positive control. After completely washingout the retigabine effect (duration: 80 s) the test substance (10 μM)was applied. The current increase induced by the test substance wasnormalised against the retigabine effect and stated as the relativeefficacy (see below).

Formalin Test in the Rat

The formalin test (Dubuisson, D. and Dennis, S. G., 1977, Pain, 4,161-174) is a model for acute and chronic pain. In the tests describedhere, the chronic pain component (phase II of the formalin test; timeinterval 21-27 min after formalin administration) was analysed.

A single formalin injection into the dorsal side of one rear paw wasused to induce a biphase nociceptive response in experimental animalsallowed to move freely, and the response was recorded by observation ofthree clearly distinguishable behaviour patterns.

Formalin is administered subcutaneously in a volume of 50 μl and aconcentration of 5% into the dorsal side of the right rear paw of eachanimal. The vehicle and the substances to be tested are administeredintravenously 5 minutes before or orally 30 minutes before the formalininjection.

The specific behavioural changes, such as lifting and shaking the paw,shifting of weight by the animal and biting and licking responses, areobserved and recorded continuously for 60 minutes after formalinadministration. The behavioural changes are weighted differently (score0-3) and a pain rate (PR) calculated using the formula below:PR=[(T ₀×0)+(T ₁×1)+(T ₂×2)+(T ₃×3)/180.

T₀, T₁, T₂, T₃ each correspond to the time in seconds for which theanimal displayed behaviours 0, 1, 2 or 3.

Sprague Dawley rats (Janvier, Belgium) are used as the phylum. Theweight of the animals is between 180 and 200 g. The group size was n=10.

Pharmacological Data

The results of the pharmacological models described above are summarisedin Table 3.

TABLE 3 Formalin test Fluorimetry Fluorimetry Patch-clamp rat i.v. %Efficacy % Efficacy % Efficacy @ 4.64 mg/kg @ 10 μM @ 1 μM Fluorimetry @10 μM % Reduction Example (Retigabine = (Retigabine = EC₅₀ (Retigabine =of nociceptive compound 100%) 100%) [μM] 100%) behaviour [%] 1 110 1.9078 40 2 10.4 17 3 134 76 1.05 4 35 11 5 69 0.083 6 73 0.075 7 12 8 63 951 0.116 10 45 0.135 11 30 12 −7 13 29 67 112 0.215 68 56 0.149 69 670.158Comparative Experiments

The substituted tetrahydroisoquinolinyl-4-oxobutyric acid amidesaccording to the invention are characterised by an improved efficacy invitro and in vivo as compared with substitutedtetrahydropyrrolopyrazines known from WO 2008/046582, as the comparativeexperiments below illustrate:

Formalin test rat i.v. @ 4.64 mg/kg Fluorimetry % Reduction of %Efficacy @ 10 μM Fluorimetry nociceptive (Retigabine = 100%) ED₅₀ [μM]behaviour [%] Example no. 2 in 115 2.81 No effect WO2008/046582 1 1101.90 40 Example no. 76 in 113 3.29 Not tested WO2008/046582 3 134 1.05Not tested

1. A substituted tetrahydroisoquinolinyl-4-oxobutyric acid amidecompound having the formula (1),

wherein R⁰ stands for C₁₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturatedor unsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; aryl orheteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₁₋₈alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; R¹ stands for F; Cl; Br; CN; C₁₋₁₀ alkyl or C₂₋₁₀heteroalkyl, each saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; C₃₋₇ cycloalkyl orheterocyclyl, each saturated or unsaturated, unsubstituted or mono- orpolysubstituted; aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted; C₁₋₈ alkyl-bridged C₃₋₇ cycloalkyl or heterocyclyl,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; C₁₋₈ alkyl-bridged heteroaryl, unsubstituted or mono-or polysubstituted, wherein the alkyl chain can be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or C₁₋₈ alkyl-bridged aryl, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be unbranched, saturated orunsaturated, unsubstituted; R² stands for H; F; Cl; Br; or C₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; or R¹ and R² together with the carbon atom bindingthem as ring member form a C₃₋₇ cycloalkyl or heterocyclyl, eachsaturated or unsaturated, unsubstituted or mono- or polysubstituted,each optionally fused to (hetero)aryl, unsubstituted or mono- orpolysubstituted; R³, R⁴, R⁵ and R⁶ each mutually independently denote H;F; Cl; Br; I; NO₂; CF₃; CN; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; —O—(C₁₋₈ alkyl)-O—; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—) N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—) N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; R⁷, R⁸, R⁹, R¹⁰ eachmutually independently stand for H; F; Cl; Br; or C₁₋₁₀ alkyl, saturatedor unsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; R¹¹ stands for H; F; Cl; Br; CN; or R⁰; R¹² stands forH; F; Cl; Br; CN; or C₁₋₁₀ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; R¹³ stands for H;F; Cl; Br; CN; C₁₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; aryl orheteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₂₋₈alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; R¹⁴ stands for H; F; Cl; Br; CN; or C₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; or R¹¹ and R¹³ together with the carbon atomsbinding them as ring members form a C₃₋₇ cycloalkyl or heterocyclyl,each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, optionally fused to (hetero)aryl, unsubstituted ormono- or polysubstituted; or R¹¹ and R¹²; or R¹³ and R¹⁴, together withthe carbon atoms binding them as ring members form a C₃₋₇ cycloalkyl orheterocyclyl, each saturated or unsaturated, unsubstituted or mono- orpolysubstituted, each optionally fused to (hetero)aryl, unsubstituted ormono- or polysubstituted; R¹⁵ stands for R⁰; wherein“alkyl-substituted”, “heteroalkyl-substituted”,“heterocyclyl-substituted” and “cycloalkyl-substituted” stand for thesubstitution of one or more hydrogen atoms, each mutually independently,with F; Cl; Br; I; CN; CF₃; ═O; ═NH; ═C(NH₂)₂; NO₂; R⁰; C(═O)H; C(═O)R⁰;CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; O—(C₁₋₈alkyl)-O; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—) S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰;S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;wherein “aryl-substituted” and “heteroaryl-substituted” stand for thesubstitution of one or more hydrogen atoms, each mutually independently,with F; Cl; Br; I; NO₂; CF₃; CN; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—) S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; said compound beingpresent in the form of an individual stereoisomer or a mixture thereof,a free compound and/or a salt of a physiologically compatible acid orbase.
 2. A compound as claimed in claim 1, wherein R¹ stands for C₁₋₁₀alkyl or C₂₋₁₀ heteroalkyl, each saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; C₃₋₇ cycloalkyl,saturated or unsaturated, unsubstituted or mono- or polysubstituted;aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C₁₋₈alkyl-bridged C₃₋₇ cycloalkyl, saturated or unsaturated, unsubstitutedor mono- or polysubstituted, wherein the alkyl chain can be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; C₁₋₈ alkyl-bridged heteroaryl, unsubstituted or mono-or polysubstituted, wherein the alkyl chain can be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or C₁₋₈ alkyl-bridged aryl, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be unbranched, saturated orunsaturated, unsubstituted; R² stands for H; or C₁₋₁₀ alkyl, saturatedor unsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted.
 3. A compound as claimed in claim 1, wherein R³, R⁴, R⁵and R⁶ each mutually independently denote H; F; Cl; Br; I; NO₂; CF₃; CN;R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰; —O—(C₁₋₈alkyl)-O—; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰ or H)₂; N(R⁰ orH)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃; SR⁰; S(═O)₂R⁰;S(═O)₂O(R⁰ or H); S(═O)₂—N(R⁰ or H)₂.
 4. A compound as claimed in claim1, wherein R⁷, R⁸, R⁹, R¹⁰ mutually independently stand for H; or C₁₋₁₀alkyl, saturated or unsaturated, branched or unbranched, unsubstitutedor mono- or polysubstituted.
 5. A compound as claimed in claim 1,wherein R¹¹ stands for H; F; Cl; Br; CN; C₁₋₁₀ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; phenyl or heteroaryl, each unsubstituted or mono- orpolysubstituted; or C₁₋₄ alkyl-bridged phenyl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted or mono- or polysubstituted; R¹³ stands for H; F; Cl; Br;CN; C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, eachunsubstituted or mono- or polysubstituted; or C₂₋₄ alkyl-bridged phenylor heteroaryl, each unsubstituted or mono- or polysubstituted, whereinthe alkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted or mono- or polysubstituted; or R¹¹ and R¹³together with the carbon atoms binding them as ring members form a C₃₋₇cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstitutedor mono- or polysubstituted, optionally fused to phenyl, unsubstitutedor mono- or polysubstituted.
 6. A compound as claimed in claim 1,wherein R¹² and R¹⁴ each mutually independently stand for H; or C₁₋₁₀alkyl, saturated or unsaturated, branched or unbranched, unsubstitutedor mono- or polysubstituted.
 7. A compound as claimed in claim 1,wherein R¹⁵ stands for C₃₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturatedor unsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl, saturated or unsaturated,unsubstituted or mono- or polysubstituted; aryl or heteroaryl,unsubstituted or mono- or polysubstituted; C₁₋₈ alkyl-bridged C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or C₁₋₈ alkyl-bridged aryl or heteroaryl, eachunsubstituted or mono- or polysubstituted, wherein the alkyl chain canin each case be branched or unbranched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 8. A compound as claimed inclaim 1, having the formula (2),

wherein R¹ stands for C₁₋₁₀ alkyl or C₂₋₁₀ heteroalkyl, each saturatedor unsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; C₃₋₇ cycloalkyl, saturated or unsaturated,unsubstituted or mono- or polysubstituted; phenyl or thienyl, eachunsubstituted or mono- or polysubstituted; C₁₋₈ alkyl-bridged C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted; C₁₋₈ alkyl-bridged phenyl, unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can be branched or unbranched,saturated or unsaturated, unsubstituted; or C₁₋₈ alkyl-bridged thienyl,unsubstituted or mono- or polysubstituted, wherein the alkyl chain canbe branched or unbranched, saturated or unsaturated, unsubstituted ormono- or polysubstituted; R³, R⁴, R⁵ and R⁶ each mutually independentlydenote H; F; Cl; Br; I; NO₂; CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ orH); C(═O)N(R⁰ or H)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—(C₁₋₈ alkyl)-O—C₁₋₈alkyl; N(R⁰ or H)₂; N(R⁰ or H)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂;SH; SR⁰; S(═O)₂R⁰; S(═O)₂O(R⁰ or H); or S(═O)₂—N(R⁰ or H)₂; R⁷, R⁸, R⁹,R¹⁰ each mutually independently stand for H; or C₁₋₄ alkyl, saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted; R¹¹ and R¹³ each independently stand for H; or C₁₋₁₀alkyl, saturated or unsaturated, branched or unbranched, unsubstitutedor mono- or polysubstituted; or R¹¹ and R¹³ together with the carbonatoms binding them as ring members form a C₃₋₇ cycloalkyl orheterocyclyl, each saturated or unsaturated, unsubstituted or mono- orpolysubstituted; R¹⁵ stands for C₃₋₁₀ alkyl, saturated or unsaturated,branched or unbranched, unsubstituted or mono- or polysubstituted; C₃₋₇cycloalkyl, saturated or unsaturated, unsubstituted or mono- orpolysubstituted; aryl or heteroaryl, unsubstituted or mono- orpolysubstituted; C₁₋₈ alkyl-bridged C₃₋₇ cycloalkyl, saturated orunsaturated, unsubstituted or mono- or polysubstituted, wherein thealkyl chain can in each case be branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or C₁₋₈alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- orpolysubstituted, wherein the alkyl chain can in each case be branched orunbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 9. A compound as claimed in claim 1, wherein R¹⁵ standsfor C₃₋₁₀ alkyl, saturated or unsaturated; branched or unbranched,unsubstituted or mono- or polysubstituted; or is selected from thefollowing substructures A, B or C,

wherein n=0, 1, 2, 3, 4, 5, 6, 7 or 8; m=0, 1, 2 or 3; ring X cancontain one or two N atoms as ring member(s); ring Y contains at least 1heteroatom selected from N, O or S and can contain up to 3 heteroatomsmutually independently selected from N, O or S; and/or can contain oneor two double bonds; R¹⁸ and R¹⁹ mutually independently denote H; F; Cl;Br; I; NO₂; CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ orH)₂; OH; OR⁰; O—(C₁₋₈ alkyl)-O; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; N(R⁰ orH)₂; N(R⁰ or H)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SR⁰;S(═O)₂R⁰; S(═O)₂O(R⁰ or H); or S(═O)₂—N(R⁰ or H)₂H; or R¹⁸ and R¹⁹together with the carbon or nitrogen atoms binding them as ring membersform an aryl or heteroaryl fused to the phenyl or heteroaryl ring, eachunsubstituted or mono- or polysubstituted; or a C₃₋₇ cycloalkyl orheterocyclyl fused to the phenyl or heteroaryl ring, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; R²⁰ and R²¹mutually independently denote H or C₁₋₁₀ alkyl, saturated orunsaturated; branched or unbranched, unsubstituted or mono- orpolysubstituted; or C₃₋₇ cycloalkyl or heterocyclyl, each saturated orunsaturated, unsubstituted or mono- or polysubstituted; or R²⁰ and R²¹together with the carbon atoms or heteroatoms binding them as ringmembers form an aryl or heteroaryl fused to ring Y, each unsubstitutedor mono- or polysubstituted; R²² and R²³ mutually independently denoteH; or C₁₋₁₀ alkyl, saturated or unsaturated; branched or unbranched,unsubstituted.
 10. A compound as claimed in claim 1, selected from thegroup consisting of:4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide;4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-Oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyricacid amide;4-Oxo-4-[1-(4-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(7-Fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3-(trifluoromethyl)benzyl)butyricacid amide;4-(5-Fluoro-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(4-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(4,4-Dimethyl-1-phenyl-1,3-dihydroisoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(7-Methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(5-Methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(3-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;N-(2-Chlorophenyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-(2,1,3-Benzothiadiazol-4-yl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-(1-Methyl-6-indazolyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-(2-Furylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-Benzyl-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acidamide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-pyridylmethyl)butyricacid amide;N-[(4-Methoxyphenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;4-Oxo-N-phenethyl-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-pyridylmethyl)butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(3-phenylpropyl)butyricacid amide;N-[2-(1H-Indol-3-yl)ethyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-methoxyphenyl)-4-oxobutyricacid amide;N-(2-Chlorophenyl)-4-(5,7-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-methyl-6-indazolyl)-4-oxobutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-furylmethyl)-4-oxobutyricacid amide;N-Benzyl-4-(5,7-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[(4-methoxyphenyl)methyl]-4-oxobutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(3-phenylpropyl)butyricacid amide;N-(4-Methoxyphenyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(2-Chlorophenyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(1-Methyl-6-indazolyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(2-Furylmethyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-Benzyl-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyricacid amide;N-[(4-Methoxyphenyl)methyl]-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyricacid amide;4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(3-phenylpropyl)butyricacid amide;N-(4-Methoxyphenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(2-Chlorophenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(1-Methyl-6-indazolyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-(2-Furylmethyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;N-Benzyl-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyricacid amide;N-[(4-Methoxyphenyl)methyl]-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyricacid amide;4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyricacid amide;4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(4-pyridylmethyl)butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-thienylmethyl)butyricacid amide;N-[(2-Chlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(2,4-Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(3,4-Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(p-tolylmethyl)butyricacid amide;N-(1,3-Benzodioxol-5-ylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(3-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(2-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(4-Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-[(2,5-Difluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;N-(1-Naphthylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyricacid amide;4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyricacid amide;4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyricacid amide;4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-propylbutyricacid amide;4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-propylbutyric acidamide;4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyricacid amide;4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4-(trifluoromethyl)-phenyl]methyl]butyricacid amide;4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)-phenyl]methyl]butyricacid amide;4-Oxo-4-(1-(2-tolyl)-6-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyricacid amide;4-(1-(2-Methyl-prop-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide;4-(1-Cyclohexyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)-phenyl]methyl]butyricacid amide; and4-Oxo-4-(1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3-(trifluoromethyl)phenyl]methyl]butyricacid amide; or a physiologically compatible salt thereof.
 11. Apharmaceutical composition comprising a therapeutically effective amountof at least one tetrahydroisoquinolinyl-4-oxobutyric acid amide compoundas claimed in claim 1 and a pharmaceutically acceptable carrier, saidcompound being present in the form of an individual stereoisomer or amixture thereof, a free compound and/or a physiologically compatiblesalt thereof, and said composition optionally further comprisingsuitable additives and/or auxiliary substances and/or optionally furtheractive ingredients.
 12. A method of treating a patient in need thereoffor a condition, comprising administering to said patient an amounteffective to treat said condition of at least onetetrahydroisoquinolinyl-4-oxobutyric acid amide compound as claimed inclaim 1, said compound being in the form of an individual stereoisomeror a mixture thereof, the free compound and/or a physiologicallycompatible salt thereof, and said condition being selected from thegroup consisting of pain, epilepsy, urinary incontinence, anxietystates, dependency, mania, bipolar disorders, migraine, cognitivediseases, dystonia-associated dyskinesias and urinary incontinence. 13.A method of treating a patient in need thereof for a condition,comprising administering to said patient an amount effective to treatsaid condition of at least one tetrahydroisoquinolinyl-4-oxobutyric acidamide compound as claimed in claim 1, said compound being in the form ofan individual stereoisomer or a mixture thereof, the free compoundand/or a physiologically compatible salt thereof, said condition beingselected from the group consisting of pain and epilepsy.